Postoperative tumor treatment strategies: From basic research to clinical therapy

Despite progression in advanced treatments for malignant tumors, surgery remains the primary treatment intervention, which removes a large portion of firm tumor tissues; however, the postoperative phase poses a possible risk for provincial tumor recurrence and metastasis. Consequently, the prevention of tumor recurrence and metastasis has attracted research attention. In this review, we summarized the postoperative treatment strategies for various tumors from both basic research and clinical perspectives. We delineated the underlying factors contributing to the recurrence of malignant tumors with a substantial prevalence rate, related molecular mechanisms of tumor recurrence post‐surgery, and related means of monitoring recurrence and metastasis after surgery. Furthermore, we described relevant therapeutic approaches for postoperative tumor recurrence, including chemotherapy, radiation therapy, immunotherapy, targeted therapy, and photodynamic therapy. This review focused on the emerging technologies used for postoperative tumor treatment in recent years in terms of functional classification, including the prevention of postoperative tumor recurrence, functional reconstruction, and monitoring of recurrence. Finally, we discussed the future development and deficiencies of postoperative tumor therapy. To understand postoperative treatment strategies for tumors from clinical treatment and basic research and further guide the research directions for postoperative tumors.


INTRODUCTION
Cancer is the highest contributor to mortality in China and developed nations. 1 The annual global incidence of cancer is increasing, placing a heavy burden on healthcare systems and threatening human health. 2The traditional treatments for tumors include surgery, radiotherapy (RT), and chemotherapy, of which surgery remains the most effective method of eradicating tumors.Surgery can be divided into radical, tumor reduction, restorative, prophylactic, palliative reduction, and diagnostic.Several animal and clinical studies have shown that adjuvant therapy administered to patients with postoperative tumors can substantially enhance both disease-free and overall survival (OS) rates. 3djuvant therapies, including postoperative chemotherapy, RT, immunotherapy, targeted therapy, and endocrine therapy, aim to eliminate any remaining cancer cells and reduce the risk of tumor recurrence or dissemination to other sites. 4lthough surgery remains the primary treatment intervention, the postoperative phase poses a possible risk for provincial tumor recurrence and metastasis.This review discusses postoperative tumor recurrence and the means of monitoring it, types and advances in postoperative oncological treatments used to prevent recurrence and common postoperative adjuvant therapies for tumors of different systems of the body, and mainly introduced applications and recent advances in biomaterials in postoperative tumor therapy.

Causes of tumor recurrence
Abnormal cell proliferation and distant metastasis are the most important features of malignant tumors.In most cases, even if the tumor is completely removed via surgery (or at least as much as possible) along with using intraoperative frozen pathology and intraoperative magnetic resonance techniques, tumor recurrence remains a risk, as patients are likely to already have microscopic metastatic foci in the bloodstream and organs, such as the liver and lungs.Therefore, patients may have recurrent metastases post-surgery, often up to 2 years. 5Postoperative tumor recurrence is divided into local, regional, and distant regeneration.Local regeneration refers to the recurrence of the tumor at the site of origin, such as within the scope of surgical resection or at a neighboring site, while regional recurrence refers to cancer cells breaking through the primary cancer area and appearing in the nearby lymph nodes or tissues.In distant regeneration, cancer cells metastasize to more distant tissues and organs (the lungs, liver, bone, or brain are commonly seen) and can be found away from the primary site; this type of recurrence is known as metastasis. 5The primary determinants influencing the postoperative recurrence of malignant tumors include the extent of residual tumor cells following surgery, malignancy of the remaining cells, and antitumor immune function. 6

Residual tumor cells
Cañellas-Socias' investigation of the single-cell transcriptomes of patients with colorectal cancer (CRC) indicated a distinct group of tumor cells, termed high-recurrence cells (HRCs).Notably, these HRCs were found to predominantly express genes associated with a poor prognosis, providing insights into the molecular basis of CRC recurrence.A humanoid mouse model of microsatellitestabilized CRC was established to study metastatic regeneration after surgical resection of recurrent CRC and its metastatic behavior.Residual HRCs in the livers of mice following initial CRC surgery yielded 33 cell categories over time, encompassing LGR5 stem cell line tumor cells, resulting in significant stage IV cancer.Employing encoding epithelial membrane protein 1 (EMP1) as a marker gene for HRCs, researchers have achieved exact tracking and elimination of this distinct cell population.
The genetic ablation of HRCs through EMP1 prevented metastatic recurrence, leading to disease-free conditions in mice following surgery.This suggests that the metastatic recurrence of CRC originates from the remaining EMP1positive cells. 7

Anesthesia
The choice of the anesthetic approach and agents used during dominant tumor surgery influences postoperative recurrence or metastasis.Distinct anesthetic and anesthesia techniques have shown deleterious effects on the immune response of patients with a tumor, subsequently increasing the likelihood of tumor recurrence and metastasis. 8However, intravenous propofol anesthesia has been shown to reduce the incidence of lung metastasis in rats. 9From a macroscopic perspective, the causes of postoperative tumor recurrence include malignancy of the tumor itself, metastasis before surgery, incomplete resection during surgery, preoperative and postoperative comprehensive treatments, weak immunity of the body, and the fact that the cancer body has not changed.Treatment of postoperative cancer recurrence is extremely challenging, and the prognosis is worse than the that of the initial diagnosis.

Infection
Bohle et al. constructed an animal model of colon cancer to explore the effect of postoperative intra-abdominal infection on angiogenesis and tumor growth.BALB/c mice were randomly assigned to two groups immediately after injection of 5 × 10 6 B51LiM cells into the cecum wall.Group 1 underwent cecal resection without postoperative infection, whereas group 2 underwent cecal resection with postoperative intra-abdominal infection.The observation duration was extended to 18 days post-cell injection and cecal resection.Group 2 infection was induced via intraperitoneal injection of 2 × 3 10 Mycobacterium fragilis colony-forming units.On perioperative day 12, the mice were sacrificed, and analysis of the results revealed that tumor recurrence was more frequent in the intraperitoneally infected animals.Throughout the execution period, the infected group displayed enhanced serum vascular endothelial growth factor (VEGF) levels, and postoperative tumor angiogenesis was augmented.These findings suggest that perioperative intra-abdominal infection contributes to increased angiogenesis and tumor recurrence following surgical resection of CRC in mice. 10iu et al. conducted a reflective assessment of 21 cases of provincial giant cell tumors in the proximal fibula from 2000 to 2021, with a distinct focus on the tibiofibular joints and the existence of residual bone.The authors focused on the underlying causes and effects of perioperative recurrence and found that postoperative local recurrence is primarily associated with the presence of residual bone fragments in the tibiofibular joint.The presence of residual bone fragments may be associated with preoperative Campanacci grading and pathologic fractures. 11Chen et al. found through animal studies that the membrane progesterone receptor, PAQR8, played a role in breast cancer recurrence, was spontaneously upregulated and copy number increased in recurrent tumors that appeared posttreatment, and was associated with a low survival rate after recurrence and low overall breast cancer patient survival.PAQR8 enhances tumor cell survival following inhibition of the estrogen receptor pathway via fulvestrant or estrogen deprivation, and blockade of the human epidermal growth factor receptor-2 (HER2) pathway by lapatinib or HER2 downregulation as well as chemotherapeutic drug treatments, which promote resistance to treatment 12 (Figure 1).Approximately 30%-40% of patients with CRC who undergo radical removal of the predominant tumor can exploit metastasis in the following years. 13

Tumor molecular mechanisms
The molecular mechanism of tumor cell generation is the mutation of cellular genes, which are normally repaired by the cellular DNA repair mechanism or induced by apoptosis through a series of pathways; however, if cells with mutated DNA are not properly processed, they transform into tumor cells.Numerous genes mutated multiple times can have a cumulative effect, leading to the creation of uncontrolled cancerous tissues. 14The genes that cause cellular carcinogenesis can be classified into three categories.The first category includes proto-oncogenes (e.g., MYC and RAS), which are activated after mutation and lead to cellular carcinogenesis.The second category is oncogenes (e.g., Rb, P53, and APC), which play opposite roles to proto-oncogenes.In normal cells, the expression of oncogenes can restrict cell division, induce apoptosis of harmful cells, and inhibit the generation of cancer cells; however, once a mutation leads to the inactivation of oncogenes, it can promote the generation of cancerous cells.The third group of genes is auxiliary genes involved in carcinogenesis, which are not directly related to carcinogenesis or inhibition of carcinogenesis, but their mutation will indirectly increase the probability of mutation of proto-oncogenes and oncogenes and will also play a role in promoting carcinogenesis. 15The 3ʹ-untranslated region (UTR) splicing events are upregulated in cancer, which enhances the expression of the key oncogene, CTNNB1, to promote tumorigenesis.Targeted inhibition of 3ʹ-UTR splicing prevents hepatocarcinogenesis 16 (Figure 2).Mutated genes and signaling pathways differ in different types of tumors.BRAF and RAS mutations play vital roles in the initiation of thyroid cancer.Moreover, the sustained presence of BRAF and RAS mutations, along with the emergence of additional mutations in Pyrrolidinedithiocarbamate ammonium, contributes to the advancement and progression of thyroid cancer.The molecular etiology of most thyroid malignancies involves aberrations in the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K)/AKT signaling cascades. 17According to genome sequencing, driver genes for non-small-cell lung cancer (NSCLC) pathogenesis exist, including EGFR, KRAS, ROS1, BRAF, NTRK, and ALK. 18The main disease mechanisms associated with intrahepatic cholangiocarcinoma include activation of the inflammation-related pathway, including JAK1/2 and subsequent phosphorylation and activation of STAT3; proliferation-related pathways, including Notch, 19 Wnt/β-catenin, 20 Hippo/YAP, and Hedgehog; and the receptor tyrosine kinase and the c-Jun N-terminal kinase /MAPK signaling pathways. 21Evidence of intra-tumor heterogeneity in hepatocellular carcinoma shows the presence of driver mutations in genes, such as TP53, CTNNB1, and TERT in the early stages of hepatocarcinogenesis 22 (Figure 3A).Most colorectal carcinogenesis is accompanied by mutations in the APC gene, which are usually accompanied by activation of the KRAS gene and suppression of the P53 oncogene 23 (Figure 3B).In addition, most older patients with CRC tend to exhibit a high degree of microsatellite instability. 24Genes involved in breast cancer progression include HER2, BRCA1, and VEGF, which participate in the PI3K-AKT-mammalian target of rapamycin (mTOR), RAS-RAF-MEK-ERK, and NOTCH signaling processes. 25Recently, several studies have shown that various circular RNAs (circRNAs) are involved in cancer promotion or suppression, to varying degrees, through different molecular mechanisms.The circRNA/Wnt axis regulates the expression of cancer-relevant genes, subsequently affecting tumor progression.Notably, cir-cRNAs showed marked enrichment in the Wnt signaling pathway.Wnt-relevant circRNAs display disordered expression in various cancer types, including digestive, respiratory, neurological, genitourinary, musculoskeletal, endocrine, and other malignancies.This approach highlights the potential of circRNAs as a diagnostic marker for cancer 26 (Figure 3C,D).
These landmark features of tumors not only represent opportunities for tumor treatment interventions, but also provide opportunities for using tumors as models to explain normal and diseased cell signaling pathways.There are many signaling pathways related to cancer, but currently research has not found a key node that can fully control cancer.I hope that with the deepening of cancer research, we can ultimately discover such key points, making cancer treatment easier and more effective.

Molecular mechanisms of tumor recurrence
With the continuous progress of molecular biological studies, such as genomics, an increasing number of mechanisms of tumor recurrence have been explored.

NSCLC
The high recurrence risk of NSCLC was related to preoperative circulating tumor DNA (ctDNA) positivity and that defects in DNA internal strand cross-linking and double-strand break repair processes increased genomic instability and were considerably associated with early NSCLC recurrence. 28Using bioinformatic methods and related analyses, Lin et al. screened for genes correlated with the risk of postoperative recurrence in lung adenocarcinoma, namely, BUB1B, BUB2, MAD1L1, CCNA, TOP2A, HMMR, MELK, and RRM2. 29

Hepatocellular carcinoma
Zhou et al. utilized genome sequencing approaches to identify five genes (WNK2, RUNX1T1, CTNNB1, TSC1, and TP53) related to initial tumor recurrence following radical resection.Among these genes, WNK2, the primary risk gene, has a tumor suppressor effect; its deactivation induces the activation of ERK1/2 signaling in hepatocellular carcinoma cells (HCCs), which is further related to tumor-associated macrophage infiltration as well as enhanced tumor growth and metastasis. 30 chain reaction to assess the expression levels of CASC2, which showed a notable downregulation of CASC2 expression in the patients with oral squamous cell carcinoma when compared with that in the healthy control group.Plasma CASC2 levels were considerably higher in patients experiencing provincial regeneration than in patients who did not, in comparison to the levels measured prior to treatment.Inducing CASC2 expression vectors engenders a substantial inhibition of tumor cell proliferation along with a decrease in miRNA-21 expression levels.These findings indicated that downregulation of the CASC2 lncRNA expression may be implicated in postoperative provincial regeneration of prior oral squamous cell carcinoma through miRNA-2. 33onducting in-depth research on upstream genes or transcription factors, such as non-coding RNAs, associated with a high risk of cancer regeneration, will help to identify related signaling pathways and novel treatment approaches.The mechanisms underlying cancer recurrence have not yet been fully uncovered.So, further studies are required to gain a complete picture of recurrence and its underlying mechanisms.Tumor recurrence is of particular interest both theoretically and practically and its understanding faces many problems which remain to be solved.From technical viewpoint, one of the most challenging issues is detection, isolation, and characterization of latent cancer cells in samples derived from patients.These cells could not be identified because they do not possess specific markers.Once isolated, the molecular properties of cancer cells need to be characterized.Currently, this could be achieved by comparative genomic hybridization approaches and gene expression array studies.For molecular characterization of tumor cells, their gene expression profile could be compared with CSCs.Another problem of cancer recurrence studies is the lack of an appropriate model.The mechanisms introduced to explain the phenomenon of tumor relapse are largely based on a limited number of experimental models.Accordingly, more models are required to advance our understanding of the basic principles of recurrence.Moreover, the identification of molecular agents involved in the activation of latent tumor cells is a requisite.Also, there is a clear need to more sophisticated imaging techniques for the analysis of tumor recurrence studies in vivo. 34

Postoperative tumor monitoring
Following surgery, patients with tumors undergo regular imaging tests, such as ultrasound, CT, or magnetic resonance imaging (MRI), to determine possible tumor recurrence.In addition to traditional imaging or endoscopy, specific tumor markers, such as carcinoembryonic antigen (CEA) and alpha-fetoprotein, can indicate the risk of tumor recurrence months before imaging changes. 35ctDNA is a potential biomarker for cancer diagnosis and prognosis as it contains tumorspecific genetic and epigenetic abnormalities.Analysis of ctDNA in post-therapeutic cancer surgery blood samples can identify high-risk patients exhibiting molecular residual disease and clinical disease recurrence 36 (Figure 4B).ctDNA is effective in detecting micro-residual disease (MRD) in many tumors, such as lung, 37 breast, 38 colon, 39 pancreatic, 40 and bladder cancers. 41Patients with cancer may benefit from ctDNA testing to identify MRD and predict postoperative recurrence.MRD testing can be used not only for early recurrence detection and adjuvant therapy, but also for the initiation and monitoring of systemic therapy and genotyping for drug resistance. 42alactose lectin-9 (Gal-9), which belongs to the animal lectin family and is characterized by a preserved carbohydrate-recognition domain, can fulfill various functional roles in tumorigenesis, primarily attributed to its galactoside binding affinity. 43Although Gal-9 is a prognostic biomarker in numerous malignancies, its role in distinct tumor types may vary.Increased Gal-9 expression has been linked to improved clinical outcomes in breast tumors, 44 melanoma, 45 squamous cell carcinoma of the cervix, 46 and hepatocellular carcinoma. 47This correlation is likely attributable to the potential anti-metastatic role of Gal-9 in the progression of these tumor types.Conversely, contradictory data indicated that high Gal-9 expression may also be indicative of a poor prognosis in hepatitis B virus-associated hepatocellular carcinoma. 48Variations in the clinical significance of Gal-9 expression can be ascribed to the heterogeneity among tumors originating from various tissues and exclusive expression methods of related ligands.
In a clinical study, Chen et al. found that the detection of serum levels of human ependynein 4 (HE4) facilitated the diagnosis and prediction of epithelial ovarian carcinoma recurrence after surgery and that a high concentration of HE4 suggested a poor prognosis. 49Laba et al. analyzed 358 individuals with clear cell renal cell carcinoma (ccRCC) undergoing nephrectomy at Renji Hospital to investigate the impact of isocitrate dehydrogenase 1 (IDH1) expression on their prognosis and reported a decrease in IDH1 expression levels in ccRCC tissues.This diminished IDH1 expression was substantially correlated with reduced OS and recurrence-free survival.The authors concluded that low IDH1 expression may be a poor prognostic biomarker for clinical outcomes in patients with ccRCC. 50

TREATMENT OF POSTOPERATIVE TUMOR RECURRENCE
Among the newly diagnosed patients with solid tumor in China, the 1-year postoperative recurrence rate is 60%. 51he 1-3 years after discharge from hospital at the end of treatment of patients with tumors is the high-risk period for recurrence and metastasis; two-third of discharged patients have developed metastasis, and after local treatment (surgery and RT) plus systemic chemotherapy, half of the patients developed subclinical occult metastasis. 52nce a tumor recurs, the difficulty of reoperation exponentially increases.In addition to reoperation, corresponding adjuvant therapies are available; however, the prognosis is much worse than that of the initial assessment.

Chemotherapy
Chemotherapy involves the use of chemical agents to impede the growth, infiltration, and metastasis of cancer cells, eventually leading to their eradication.This therapeutic modality operates at the systemic level. 53In 1946, nitrogen mustard (HN2) was used to treat malignant lymphoma with short-lived efficacy 54 ; in 1948, methotrexate was used to treat acute lymphoblastic leukemia, which preluded modern cancer chemotherapy. 55atients diagnosed with pancreatic cancer often experience postoperative recurrence.In cases where recurrence is localized, several therapeutic modalities have been investigated, including continual surgical resection, RT, and standalone chemotherapy.Despite surgical resection becoming the primary option for cure, it is considerably challenging to completely eliminate the disease through reiterated resection in individuals with localized regeneration of pancreatic cancer.Gemcitabine (GEM)-based chemotherapy is a therapeutic option for postoperative regeneration of pancreatic cancer. 56Systemic chemotherapy has become the prevailing treatment approach for individuals with distant recurrence; multiple regimens have markedly demonstrated efficacy in improving survival outcomes in patients with recurrent pancreatic cancer. 57isplatin/carboplatin-based chemotherapy regimens have been employed as therapeutic approaches for managing the perioperative regeneration of NSCLC. 58Combined concurrent RT is another promising treatment option for selected patients with recurrent NSCLC. 59Recurrent peritoneal metastasis is the most common and important lethal factor following surgery for progressive gastric cancer.Yan et al. conducted a descriptive case series study to investigate the efficacy of bidirectional intraperitoneal and systemic chemotherapy (BIPS) for the treatment of recurrence and demonstrated that paclitaxel (PTX)-based BIPS was effective and safe for recurrent peritoneal metastasis of gastric cancer. 60

Radiotherapy
RT is a type of local treatment utilizing high-energy radiation to treat tumors; after repeated killing, the tumors gradually become smaller. 61hanson et al. concluded that surgical intervention is the preferred therapeutic approach for managing nonfunctioning pituitary adenoma (NFPA).RT may be considered in cases of residual perioperative growth or tumor regeneration.The role of RT in the perioperative management of NFPA remains controversial.The primary arguments opposing the standard application of RT include the absence of randomized controlled trials, utilization of clinically irrelevant endpoints in most RT studies, benign nature of the condition, potential for RT-induced side effects, and the possibility of administering RT at a later phase.Nevertheless, owing to its substantial efficacy in suppressing tumor growth, diminishing tumor volume, and improving visual shortfalls, along with its relatively hindered adverse effects, RT plays a notable role in the treatment of NFPA when residual tumors continue.When examining the RT process, several factors must be carefully considered, such as the size of the remaining tumor, its proximity to the optic pathway, and the possible risk it poses to the adjacent healthy tissue. 62Pagliara et al. suggested that topical agents may be used for the primary or secondary treatment of conjunctival squamous cell carcinoma using mitomycin C, 5-fluorouracil, and interferon α-2b (IFN-α-2b).Plaque interventional RT can be used to control residual microscopic tumors following surgical resection of conjunctival squamous cell carcinoma or in cases of deep scleral or corneal invasion. 63Ito et al. concluded that salvage-synchronized RT (60 Gy, 30 sessions) combined with 3D conformational RT along with 5-fluorouracil/platinum-based chemotherapy is a viable and secure therapeutic approach for local and regional regeneration following the curative removal of esophageal squamous cell carcinoma.This treatment method showed considerable efficacy, especially in patients displaying near-complete remission. 64he radiation used in traditional RT is penetrating, and the radiation that reaches the tumor in the body needs to pass through the skin and other normal tissues and organs.The ionizing radiation can also damage the normal tissues before and after the tumor.In recent years, the combination of RT and biomaterials targeting tumor tissue therapy has become a research hotspot.This method can reduce side effects and increase treatment efficiency. 65

Immunotherapy
Tumor immunotherapy is a systemic treatment that relies on autoimmune functions to kill cancer cells and tumor tissues by activating the immune system. 66Coley pioneered an immunotherapeutic strategy aimed at activating the patient's immune system to cure tumors. 67n the 1980s, recombinant versions of the cytokines IFN-α and interleukin 2 (IL-2) were approved by the Food and Drug Administration for utilization in cancer immunotherapy. 68Subsequently, more cytokines, 69 antibody classes, 70 tumor vaccines, 71 adoptive cell therapies, 72 and oncolytic viruses 73 have been developed for cancer immunotherapy through continuous and in-depth research.
Cheng et al. investigated a patient with a BRAF mutation and DNA mismatch repair-deficient CRC who experienced perioperative regeneration and abdominal and pelvic metastases.Notably, the patient achieved remission after treatment with the novel anti-programmed cell death 1 (PD-1) antibody, BGB-A317. 74Zhu et al., who cured patients with provincially regenerating pancreatic cancer treated with systemic RT plus pembrolizumab and trametinib, proposed that this combination may be a novel treatment approach, but a phase 3 trial remains warranted to confirm this finding.56a In a phase 1 clinical trial, Duerinck et al. reported that intraoperative injections of an anti-cytotoxic T lymphocyte-associated antigen-4 monoclonal antibody (mAb) ipilimumab and an anti-PD-1 mAb nivolumab following resection of recurrent glioblastoma were both feasible and safe. 75Heat shock protein 70 (HSP70) is an antigenic protein in hepatocellular carcinoma. 76Therefore, Matsui et al. developed an HSP70 mRNA-transfected dendritic cell (DC) treatment for individuals with unresectable or regenerated HCC and completed a phase 1 trial. 77Through a case study, Takami et al. indicated that nivolumab could likely benefit distinct patients with developed or regenerated gastric cancer.Despite the generally poor prognosis of gastric cancer and peritoneal dissemination, multidisciplinary treatment involving nivolumab may extend patient survival. 78

Targeted therapy
Targeted therapy approach focuses on distinct oncogenic sites at the cellular and molecular levels, which may involve targeting protein molecules or gene fragments within the tumor cell.Therapeutic drugs target and bind to oncogenic sites; the targeted interaction causes the drugs to act selectively at the tumor site, leading to the spe-cific elimination of tumor cells, while not affecting healthy tissue cells surrounding the tumor. 79ian et al. reported a case of regenerate HCC, accompanied by tumor thrombi in the right atrium (RA) and inferior vena cava (IVC).The patient underwent palliative RT alongside the integration of pembrolizumab and lenvatinib, leading to the amelioration of disease symptoms, including bilateral lower extremity edema.HCC with RA and IVC tumor thrombus showed shrinkage at the latest assessment, and the patient displayed a progression-free survival exceeding 7 months with no adverse events of grade ≥3.Qian et al. proposed that a treatment regimen involving cancer thrombus-directed RT, pembrolizumab immunotherapy, and lenvatinib-targeted therapy may be a viable strategy for managing this subset of patients with recurrent HCC. 80Given that regenerated distinct cell carcinoma does not respond well to chemotherapy and lacks standard treatment, Tao et al. reported a case study of a patient with recurrent renal clear cell sarcoma following open radical nephrectomy.After the failure of chemotherapy alone, the patient underwent six course treatment with combination chemotherapy with lenvatinib.At the 8month perioperative follow-up, the tumor size displayed a notable decrease, and surgical resection was conducted on the recurrent tumor as well as a portion of the liver.No signs of tumor regeneration or metastasis were observed during the assessment. 81

Photodynamic therapy
Photodynamic therapy (PDT), a chemotherapy produced by light excitation, destroys tumors or other pathological target tissues through selective photosensitization of the local area of the lesion.Through the photosensitizermediated and oxygen molecule-involved energy and/or electron transfer, PDT produces reactive oxygen species (ROS) with cytotoxicity in the diseased tissues (such as single-linear oxygen species and free radicals), which destroy the framework of the organelles at the target site through oxidative damage, inducing apoptosis alongside necrosis of target cells. 82he application of PDT to gynecological malignancies is a new and innovative approach primarily utilized in palliative care.At the Roswell Park Cancer Institute, the integration of PDT into gynecologic cancer treatment was initiated during the mid-1980s.Thirty-five patients have undergone PDT for regeneration or metastatic cutaneous and vulvar, vaginal, anal, or cervical regeneration.Empirically, the complete reaction was examined in 85% of the patients with metastatic skin lesions.Among individuals with metastatic vaginal and cervical cancer, 27% exhibited a complete reaction to the treatment, with a median reaction time of 28 months.
However, the therapy was associated with various side effects, such as mild-to-intense burning sensations at the therapy site, pain, and edema.Several patients receiving treatment for skin lesions and lower genital tract recurrences required narcotic pain medications to control these symptoms.PDT is a viable alternative for patients unfit to undergo conventional treatments or those seeking to reduce the use of conventional treatment in lieu of less invasive treatment modalities. 83Chen et al. reported that the use of percutaneous transhepatic cholangioscopy-guided PDT following percutaneous transhepatic cholangiocarpal drainage (PTCD) substantially extended postoperative survival of patients with recurrent extrahepatic cholangiocarcinoma compared with the use of PTCD alone.Furthermore, PDT contributes to enhancing the quality of life of patients by expediting the timely removal of PTCD drains. 84owever, high toxicity, moderate efficacy, and low uniformity in shape remain critical unresolved issues that hamper the clinical application of (photodynamic therapy) PDT.In recent years, researches on the application of nanomaterials in tumor PDT and photothermal therapy (PTT) have emerged one after another, which to some extent solves the potential problems of traditional therapy. 85

EMERGING POST-SURGICAL TUMOR TREATMENT TECHNOLOGIES
Technologies related to postoperative tumor therapy have been developed to improve treatment outcomes, reduce side effects, and provide patients with individualized treatment options.In the following section, we introduce emerging postoperative tumor treatment technologies in detail in terms of the prevention of recurrence, functional reconstruction, and monitoring of recurrence.

Postoperative treatment to prevent recurrence
Zhang et al. constructed a layered cisplatin-loaded fiber/sponge complex (CFSC) that integrated chemotherapy and hemostasis.The resulting embeddable CFSC could perform concurrent hemostasis and obtain disseminated tumor cells after tumor resection, with the continuous release of provincial residual tumor cells and those accumulated within the complex, thereby impeding provincial tumor recurrence and remote tumor metastasis in hypodermic postoperative recurrence and metastasis models 86 (Figure 5A,B).Zhang et al. developed a potent symbiotic immunotherapeutic system using an insertable sodium alginate (SA) hydrogel to concurrently impede in situ recurrence and metastasis.In the process of synthesizing injectable SA hydrogel microsystems, researchers have incorporated Toll-like receptor (TLR) agonists (CpG ODNs) to effectively impede in situ recurrence.Subsequently, a CEA probe was introduced to facilitate the detection of CEA using the fluorescence resonance energy transfer (FRET) technique, thereby enabling the monitoring of the onset and progression of tumor recurrence.Conversely, a new approach was introduced to prepare indocyanine green-loaded anti-programmed cell death 1 ligand 1 antibody (anti-PD-L1)-modified SA nanogels (indocyanine green (ICG)@SA-anti-PD-L1 nanogels) to facilitate diagnostic and inhibitory functions against lung metastasis.These nanogels serve as ancillary in situ tumor therapies, potentially addressing lung metastasis 87 (Figure 5C,D).
Li et al. engineered surgical tumor-derived cell membranes (CMs) incorporating resorcylic acid (R848)-loaded mesoporous polydopamine (MPDA) nanoparticles to create personalized photothermal nanovaccines that offer targeted tumor photothermal immunotherapy and prophylactic benefits.The prepared photothermal nanovaccine, MPDA-R848@CM (MR@C), showed excellent photothermal immunotherapeutic effects under imaging guidance, eradicating firm tumors under near-infrared laser exposure and additionally suppressing metastatic tumors through the resulting antitumor immunity, especially in conjunction with programmed death ligand 1 antibody therapy (aPD-L1).In addition, the findings of an in vivo preventive assay confirmed that vaccination with photothermal nanovaccines resulted in 4% prevention of 1T100 cell re-excitation in a postoperative tumor model. 88Zhang et al. devised a dual-function platform using gold nanorods (AuNRs) to develop two distinct therapeutic and diagnostic agents.The first agent involved a combination of AuNRs and quantum dots to detect CEA via FRET, indicating the onset of in situ regeneration, while the second agent solely utilized AuNRs for PTT in conjunction with anti-PDL1-mediated immunotherapy, engendering the suppression of the tumor metastatic process.Successive evaluations revealed that combined immunotherapy exhibited a synergistic effect, leading to tumor cell death and increased generation of CD3/CD4 and CD3/CD8 T lymphocytes, resulting in greater secretion of immune factors (IL-2, IL-6, and IFN-γ) than that generated via monoimmunotherapy.This synergistic immunotherapy solution can serve multiple purposes, including diagnosis and treatment of postoperative tumor recurrence 89 (Figure 6).that effectively inhibited the recurrence and metastasis of B16F10 or 4T-1 tumors following surgery.Overextended treatment durations and immunotherapy for melanoma and breast cancer demonstrated substantial efficacy, leading to a notable reduction in the risk of cancer metastasis and recurrence. 93The prevention of postoperative tumor recurrence and metastasis using conventional implantable devices remains a great challenge owing to their inability to manipulate several drug releases.An implantable multistage structured microfiber device with time-programmed drug release for ancillary chemotherapy following local-ized breast cancer surgery was developed.The structure was obtained using a coaxial electrostatic spinning technique through the creation of regularly managed chambers within the fiber matrix.The rapid discharge of DOX hydrochloride from the chambers killed residual tumor cells, thus impeding tumor regeneration.The fibrous matrix kept releasing the matrix metalloproteinase-2 inhibitor disulfiram, which hindered tumor invasion and impedes metastasis.The fibrous devices implanted in homozygous mice after the surgical shrinkage of tumors show outstanding therapeutic efficacy by blocking regeneration and metastasis. 94 human IL-4 to trigger the differentiation of DCs from peripheral blood mononuclear cells and applied autologous HCC lysate sensitization to these DCs, targeting hepatic recurrence and metastasis.The authors reported a reduced rate of metastasis and recurrence in the DC tumor vaccine group in contrast to the chemotherapy group, along with a higher survival rate in the DC tumor vaccine group than in the chemotherapy group, indicating the likelihood of enhancing patient immune response, reducing the rates of metastasis and recurrence, and increasing OS rates.This is a promising therapeutic approach to prevent postoperative recurrence in patients with hepatocellular carcinoma. 97Zhang et al. successfully prepared amphiphilic Janus nanoparticles (JNPs) using a simple and reproducible method for the specific targeting of postoperative residual HCCs and introduced the surfaces of AuNRs via lactobionic acid (LA), resulting in the development of LA-JNPs.Researchers have developed an effective and site-specific co-delivery system capable of delivering both hydrophilic and hydrophobic drugs within distinct compartments, thus hindering potential interactions between them.By utilizing a postsurgical model of hepatocellular carcinoma recurrence, the combined mechanisms of enhanced permeability and retention effect-based tumor targeting, along with LA-based active targeting, work synergistically to promote the accumulation and internalization of JNPs at the tumor site.LA-JNPs presented a targeting platform for the co-delivery of sorafenib and DOX, exhibiting optimal anti-regenerative effects and enhancing survival in mice 98 (Figure 10).

HCC
Unavoidable hemorrhage throughout tumor resection notably enhances the susceptibility to tumor recurrence because cancer cells can metastasize through the bloodstream. 99Accomplishing effective hemostasis and impeding postoperative tumor regeneration remain challenging, while biomaterial approaches of fast hemostasis and simultaneous impedance of tumor regeneration during tumor resection have rarely been reported.Liang et al. presented a comprehensive therapeutic approach by introducing a multinetwork cryogel enhanced with ZIF-8 nanoparticles.This new approach allows for accelerated hemostasis via intraoperative blood-triggered shape recovery and enhanced coagulation.In vitro experiments demonstrated that the QCSG/HA-DA/ZDH (QH/ZDH) cryogel efficiently induced the death of cancer cells through the emergence of active oxygen species under ultrasound stimulation, while resection in ectopic hepatocellular carcinoma reduced the rate of tumor recurrence, providing further validation of the promising impact of the QH/ZDH cryogel.This cryogel operates through a comprehensive approach involving intraoperative hemostasis and perioperative acoustic kinetic treatment with pHresponsive HMME release to effectively prevent recurrence.This integrated strategy has substantial potential for clinical applications.groups was modified to enable the concurrent delivery of small interfering RNA against glutathione peroxidase 4 (si-GPX4) and cisplatin (Pt) with substantial drugloading efficiency.The folic acid/Pt-si-GPX4@IONPs demonstrated notable effectiveness against glioblastoma including U87MG and P3 GBM cells.Upon cellular breakdown, IOPs dominantly enhanced iron (Fe 2+ and Fe 3+ ) concentrations, while Pt-induced detrimental effects on nuclear and mitochondrial DNA, consequently inducing apoptosis.Ionophore-enhanced H 2 O 2 increased the levels of reduced nicotinamide adenine dinucleotide phosphate oxidase through activation.The interplay of Fe 2+ , Fe 3+ , and intracellular H 2 O 2 in the Fenton reaction leads to ROS production, triggering iron death; however, the simultaneous release of si-GPX4 suppresses GPX4 expression, which enhances therapeutic efficiency through a mechanism related to iron-induced cell death 102 (Figure 11C,D).

Postoperative functional reconstruction
The reconstruction of bone defects after bone tumor resection is a great challenge in clinical treatment, and a variety of reconstructive repair methods have been introduced.Some emerging materials play a role in functional reconstruction following bone tumor surgery. 103Jayash et al. found that osteoblast inhibitory factors in lowmolecular-weight chitosan matrices promoted cell growth and proliferation and increased osteoblastin and osteocalcin levels. 104Lu et al. designed a novel magnetic SrFe 12 O 19 nanoparticle-modified mesoporous bioglass/chitosan scaf-fold.The authors revealed that the incorporation of magnetic SrFe 12 O 19 nanoparticles within the scaffold notably enhanced the osteogenic differentiation of stem cells and prompted the generation of new bone by activating the bone morphogenetic protein 2/Smad/runt2 pathway.However, the magnetic field generated by the magnetic scaffold accelerated the formation of phosphate during osteogenesis, thereby promoting mineralization. 105Similarly, Yang et al. prepared multifunctional magnetic mesoporous calcium silicate/chitosan (MCSC) scaffolds via a freezedrying method using SrFe 12 O 19 , CaSiO 3 , and CS as raw materials to investigate their suitability for bone repair and antitumor ability.The ability of synergistic photothermal chemotherapy against osteosarcoma was verified using a xenograft mouse bone tumor model.Bone volume per tissue volume, bone density, micro-CT scanning, Van Gieson's picrofuchsin staining, and calcein fluorescence experiments further demonstrated that bone marrow mesenchymal stem cell (MSC)-loaded MCSC scaffolds could effectively promote osteogenesis.This suggests that MCSC scaffolds have great potential for treating bone tumorrelated defects. 106Lu et al. fabricated scaffolds composed of zoledronic acid-containing chitosan nano-hydroxyapatite (CS/nHA/Zol) and used the standard cell counting kit-8 method to investigate the antitumor effects of various scaffold materials on the proliferation of bone giant cell tumor cells.The authors found that CS/nHA/Zol scaffolds exerted an antitumor effect by inducing apoptosis in osteoblastoma cells while simultaneously attenuating their osteoclastic activity.This inhibition reduced osteoblastoma cell proliferation.Furthermore, cytotoxicity assessments demonstrated favorable biocompatibility of the CS/nHA/Zol scaffolds.Moreover, the incorporation of Zol into CS/nHA did not impede osteogenic differentiation, while the CS/nHA/Zol scaffolds exhibited favorable osteoinductive properties. 107Dang et al. fabricated CuFeSe 2 nanocrystalline-functionalized BG scaffolds by integrating 3D printing technology with a solvothermal method.The authors utilized the photothermal effect of BG-CFS scaffolds to eliminate bone tumor cells in vitro.Furthermore, the capacity of BG-CFS to induce apoptosis in Saos-2 tumor cells was validated in vivo.In both the in vivo and ex vivo experiments, BG-CFS scaffolds promoted the adhesion and proliferation of bone marrow mesenchymal stem cells (BMSCs), stimulated osteogenic differentiation of BMSCs in vitro, and initiated bone regeneration in vivo. 108Palama et al. showed that microporous polycaprolactone scaffolds offer structural support for the attachment, proliferation, and osteogenic differentiation of osteoblast-like cells.The endopore to enable localized dexamethasone (DXM) release and maintain its sustained delivery.The microporous scaffolds exhibited proficient utilization of DXM as a localized tumor therapy and facilitated in vitro proliferation and differentiation of osteoblast-like cells. 109Raucci et al. discovered that the exfoliation of black squamous material effectively inhibited the metabolic activity of tumor cells.This inhibition was achieved through an increase in the production of reactive oxygen radicals, specifically in osteosarcoma Saos-2 tumor cells, even in the absence of treatment.Notably, the same exfoliated material could stimulate both the proliferation and osteogenic differentiation of human osteoblasts, while promoting the replication and osteogenesis of human BMSCs. 110Zhang et al. fabricated hydrogenated black titanium dioxide coatings featuring a micro/nanograded morphology using an inductively suspended plasma spraying technique and demonstrated effective and controllable inhibition of tumor growth both in vitro and in vivo when exposed to 808 nm near-infrared laser irradiation.
Additionally, micro-and nanostructured surfaces, along with the presence of Ti-OH groups, facilitate favorable adhesion, proliferation, differentiation, and osteogenic gene expression in rat BMSCs 111 (Figure 12A).Liao et al. constructed a dual-purpose hydrogel by integrating methacrylated gelatin and methacrylated chondroitin sulfate enhanced with AuNRs and nanohydroxyapatite (nHA), which displayed notable photothermal effects.This innovative design effectively eliminated perioperative residual tumors and prevented bone recurrence.In laboratory experiments, the application of hybridized hydrogels eradicated K7M2wt cells (a mouse bone tumor cell line) through photothermal therapy.Simultaneously, the hydrogel emulated the features of the extracellular matrix, promoting the proliferation and osteogenic variation of MSCs.Thus, mixed hydrogels, with their dual functions of tumor treatment and bone recurrence, show excellent potential for the treatment of bone tumors and offer a new treatment approach for tumor-associated complicated bone diseases. 112The use of these materials in bone tumorrelated therapy has rarely been reported, although they have attracted attention.With additional extensive investigations, they may possibly serve as candidate replacements for bone defects following tumor resection.
Three-dimensional printing has been used to design a custom-designed prosthesis infused with PTX and DOX drugs to mitigate the risks of tumor recurrence and metastasis following breast cancer-related surgery.Drug release revealed that the 3D-printed prosthesis incorporating PTX and DOX microspheres showed constant drug release for more than 3 weeks.Extended release effectively inhibits cancer recurrence beyond the critical threshold while minimizing adverse side effects at the same time 113 (Figure 12B-D).
Approximately 70% of patients with breast cancer experience bone metastases.Therefore, 3D printing technology and nanoinks have been used to create multifunctional scaffolds.This novel strategy can accomplish two essential objectives, namely eradication of neoplastic cells and restoration of tumor-associated bone defects.Metallic polydopamine (PDA) nanoparticles (FeMg-NPs) exhibit efficient encapsulation and release of metal ions Fe 3+ and Mg 2+ in their local environment.Fe 3+ contributes to chemodynamic treatment by synergistically enhancing PDA-induced photothermal therapy, which leads to highly effective photothermal conversion under near-infrared laser irradiation and the eradication of bone metastatic tumors.Concurrently, the precise and extended release of osteoinductive Mg 2+ from a 3D scaffold with bone porosity stimulates new bone formation within the bone defects.In summary, implantation of scaffolds from nanoinks containing FeMg-NP (FeMg-SC) through 3D printing can simultaneously eradicate bone metastatic tumors and repair tumor-associated bone defects. 114i et al. developed a smart hydrogel patch with the ability to regulate the plasticity of tumor-initiating cells (T-ICs) induced in the context of triple-negative breast cancer (TNBC) within the TME.The T-ICs show insensitivity to hormone and HER2 targeting.In a chemoresistant TNBC mouse model, the in situ generation of hydrogel networks targeted and treated tumors while simultaneously detecting intratumoral ROS, leading to both cleavage of the hydrogel network and controlled release of the therapeutic payload.The implementation of a patch designed to hinder the activity of the histone demethylase lysinespecific demethylase 1 (LSD1) engendered the epigenetic regulation of the transition of T-ICs from self-renewal to differentiation, thus restoring their chemosensitivity.Fur-thermore, the hydrogel patches were explored to enhance tumor immunogenicity and promote infiltration of T cells via epigenetically activating innate immunity.A singledose hydrogel -/+5 patch containing LSD1 inhibitors and chemotherapeutic agents inhibited tumor recurrence and metastasis following surgery 115 (Figure 13).

Postoperative monitoring for recurrence
Li et al. developed a set of lncRNA markers as potential dependent molecular indicators for predicting early recurrence in individuals with muscle-invasive bladder cancer.This innovative approach can improve clinical decision making and, ultimately, enhance patient outcomes. 116He et al. found that patients diagnosed with postoperative recurrence of prostate cancer had high levels of serum miR-148a-3p and low levels of miR-485-5p.It has been demonstrated through receiver operating characteristic assessment that the concurrent measurements of miR-148a-3p and miR-485-5p are potential sensitive and specific diagnostic biomarkers for postoperative recurrence of prostate cancer. 117Hou et al. used signatera-ctDNA technology to evaluate the role of ctDNA in the detection and prediction of the recurrence of MRD in patients with epithelial ovarian cancer and found that the specificity and sensitivity of recurrence detection were 100%. 118eanwhile, Zhang et al. investigated and designed a highly effective synergistic immunotherapy system based on injected SA hydrogel, which could concurrently hinder in situ regeneration and metastasis.The authors constructed an injectable hydrogel microsystem consisting of SA and incorporated TLR agonists (CpG ODNs) to hinder the in situ regeneration of tumors.Consequently, they introduced a CEA probe into the system, utilizing the FRET technique for real-time monitoring of tumor recurrence initiation and progression.Alternatively, the authors designed a nanogel formulation (ICG@SA-anti-PD-L1 nanogel) by incorporating ICG and anti-programmed cell death 1 ligand 1 antibody (anti-PD-L1) into a revised SA nanogel to diagnose and prevent lung metastasis through ancillary in situ tumor therapy. 87eng et al. assessed the SA micro/nanosystem both in vitro and in vivo and demonstrated its capability to monitor and hinder postoperative regeneration and metastasis.The authors proposed a novel approach employing polyether ether ketone on a highly crosslinked polyethylene knee implant model for in vivo MRI monitoring of the periprosthetic region without metal artifacts, enabling the use of MRI to observe bone formation and healing near prosthesis, along with detecting potential indications of infection and tumor recurrence following total knee arthroplasty. 119RISPR/Cas system is widely applied in emerging gene detection technologies. 120Chen et al. developed a fast and ultra-sensitive electrochemical biosensor to achieve high sensitivity, the ability to distinguish variants, and the goal of directly detecting RNA in viruses, 121 and they also presents an unprecedented variants gene detection platform (Methodologies of Photonic CRISPR Sensing), which achieved high specificity and sensitivity at the same time by the innovative crossover of the unique sequencespecific recognizing ability of the CRISPR/Cas system and the superior sensitivity of the surface plasmon resonance sensing technique. 122Chen et al. developed CRISPRpowered optothermal nanotweezers, with high specificity and feasibility in in situ manipulation and identification of biological nanoparticles, CRISPR-powered optothermal nanotweezers could become a universal tool for real-time diagnosis, biophotonics, and biological nanotechnology. 123heng et al. developed a highly sensitive CRISPRempowered surface plasmon resonance sensor for diagnosis of inherited diseases with femtomolar-level real-time quantification. 124

Others
Advancements in "black bioceramics" have broadened their application spectrum, shifting from tissue regeneration to disease treatment, signifying a highly promising progression in this domain.The successful synthesis of black bioceramics has been achieved through the Mg thermal reduction of conventional white ceramics, including silicate-based materials (such as CaSiO 3 and MgSiO 3 ) and phosphate-based materials (such as Ca 3 (PO 4 ) 2 and Ca 5 (PO 4 ) 3 (OH)).The photothermal functionality of black bioceramics is ascribed to the presence of oxygen vacancies and structural defects, allowing them to retain their original high biological behavior and regenerative potential.They showed outstanding photothermal antitumor effects against skin and bone tumors.Simultaneously, they notably enhance the bioactivity of skin and bone tissue fixation in vitro and in vivo 125 (Figure 14A,B).Wei et al. designed a degradable microrobot guided by magnetic forces and imaging that effectively transported engineered stem cells for in situ hepatic tumor therapy.The microrobot has a burr-like porous spherical structure crafted from synthetic composites, ensuring simultaneous degradability, mechanical strength, and magnetoactivation capabilities.During preclinical studies performed in nude mice, a microrobot containing the cells was administered via the portal vein, and upon release, cells significantly impeded tumor growth 126 (Figure 14C,D).The increasing interest in 3D tumor models for life science applications stems from their ability to precisely mimic the physiological conditions of the in vivo TME.Therefore, these models have remarkable potential as guides for drug screening. 127Samara et al. presented a viable, durable, and cost-effective approach employing a paper-based platform to create cryopreservable arrays of high-throughput 3D tumor models.The paper-based cryopreservable arrays of 3D models provide an efficient platform to assess tumor response to cisplatin drug therapy while replicating key features of in vivo tumors that are absent in conventional 2D cultures.They provide a low-cost, simple, and rapid experimental process and enable cryopreservation and thawing of 3D tumor arrays for on-demand use. 128Antunes et al. utilized a superhydrophobic surface for the rapid preparation of airborne HA-methacrylate (HA-MA) alongside gelatin-MA photocrosslinked 3D spheroidal microgels.These systems have been used to simulate diverse 3D co-cultures of prostate cancer cells and human osteoblasts, which allowed for the exploration of cellular heterogeneity and the tumorextracellular matrix microenvironment, providing valuable insights into prostate cancer and bone metastasis interactions.The solvent-free, air-generated 3D microgel microenvironments serve as an efficient tumor simulation platform for in vitro high-throughput screening of therapies that target the microenvironment of prostate bone metastasis 129 (Figure 15A).Chemotherapy resistance is a major challenge 130 ; therefore, Wang et al. devised an innovative differentiation uptake strategy that allowed for the efficient and comprehensive isolation of genuinely drugresistant (DR) cells from a wide array of drug-surviving cancer cell types consisting of PTX-surviving human ovarian cancer cells, human lung cancer cells (A549/PTX), and adriamycin-surviving human immortalized bone marrow leukemia cells (K562/ADR).Notably, the subpopulation displaying lower fluorescence consisted of DR cells, whereas the subpopulation exhibiting higher fluorescence consisted of non-DR cells.Additionally, DR cells and their progeny were captured to show increased expression of

CONCLUSIONS
Well-defined surgical resection, augmented by comprehensive multidisciplinary collaboration, is essential for achieving optimal results in patients with removable cancers.Clinical disadvantages, such as a high tumor load, vascular invasion, lymph node metastasis, and positive margins are common, and even after surgical resection, the percentage of local recurrence, lymph node metastasis, and distant metastasis remains high, and the prognosis is poor.
The implementation of postoperative tumor treatment has shown effectiveness in enhancing the local regulation rate of tumors, thus holding significant importance in the management of locally advanced tumors.Clinically, appropriate adjuvant therapies can be selected according to the tumor site, pathological type, gene mutation status, and biological behavior.In this review, we summarized the macroscopic causes of malignant tumor recurrence, related molecular mechanisms, molecular mechanisms of tumor recurrence after surgery, and related postoperative means of monitoring recurrence and metastasis to identify therapeutic targets and guide clinical research.We also described the relevant treatment methods for postoperative tumor recurrence, including chemotherapy, RT, immunotherapy, targeted therapy, and PDT.There have been few studies on treatment strategies for postoperative tumor recurrence, which may be related to the fact that most patients with postoperative recurrence choose palliative treatment; therefore, further investigations are warranted.Subsequently, we introduced traditional clinical postoperative treatment strategies for several types of malignant tumors with high incidence rates to hinder perioperative regeneration and metastasis, including lung, breast, pancreatic, esophageal, and endometrial cancers.There are different postoperative treatment strategies for different types and stages of tumors.We focused on the emerging technologies used in postoperative tumor treatment in recent years from the perspective of functional classification, including the prevention of postoperative tumor recurrence, postoperative functional reconstruction, and postoperative recurrence monitoring.Relevant biomaterials have considerable potential for postoperative tumor therapy.
However, there remain some deficiencies in postoperative tumor therapy.Traditional RT and immunotherapy have substantial side effects, cause great damage to organs, and are easily tolerated.The efficacy of a single postoperative tumor therapy is limited, and various methods should be used in combination to further improve therapeutic efficacy.The molecular mechanism underlying cancer recurrence requires further research to identify more precise therapeutic targets.Future studies should also focus on the molecular mechanisms underlying tumor recurrence and the corresponding therapeutic strategies to provide diversified tumor treatment options.Postoperative cancer treatment modalities and protocols remain controversial, and randomized clinical studies are required to explore their long-term effects.Furthermore, it is imperative to consider not only the effectiveness along with secured data but also the indicators.Crucial assessments of data from upcoming clinical trials and translational studies are essential and will facilitate the formulation of research inquiries to enhance postoperative treatments for tumors to improve patient prognosis.

C O N F L I C T O F I N T E R E S T S TAT E M E N T
The authors declare no conflict of interest.

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I G U R E 2 (A) Enrichment of the CTNNB1 3′ FL transcript by U1 snRNP RIP.(B) Effect of overexpressing CTNNB1 on exogenous CTNNB1.(Reprinted with permission from Publisher [ref.16])

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I G U R E 3 (A) Signaling pathways involved in cholangiocarcinoma.(Reprinted with permission from Publisher [ref.22]) (B) Diagram of progression of colorectal cancer.(Reprinted with permission from Publisher [ref.23]) (C) Mechanism of Wnt-relevant circular RNAs (circRNAs) in gastric carcinoma.(D) Mechanisms of Wnt-relevant circRNAs in lung cancer.(Reprinted with permission from Publisher [ref.26])

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I G U R E 5 (A) Schematic illustration of cisplatin-loaded fiber/sponge complex (CFSC) combining hemostasis and chemotherapy.(B) In vivo efficacy evaluation of CFSC on postoperative 4T1/green fluorescent protein (GFP) model.(Reprinted with permission from Publisher [ref.86]) (C) Schematic diagram of the efficient synergistic immunotherapy via indocyanine green (ICG)@SA-anti-programmed cell death 1 ligand 1 (PD-L1) nanogels.(D) Highly effective synergistic immunotherapy based on sodium alginate (SA) gel 1 and SA nanogel 2. (Reprinted with permission from Publisher [ref.87]) 4.1.1Breast cancer Lu et al. developed micellar nanoparticles composed of chitosan oligosaccharide all-trans retinoic acid coated with hyaluronic acid (HA), which encapsulated the doxorubicin (DOX) to form HA@CA/DOX NPs.The deliquescent component, chitosan oligosaccharide, and the deliquescent component, all-trans retinoic acid (ATRA), inhibited the nuclear factor kappa-light-chain-enhancer of activated B cells inflammation-related activation pro-cess in 4T1 tumor cells and myeloid-derived suppressor cells (MDSCs), thereby decreasing postoperative inflammation following resection.In addition, ATRA reduced MDSCs within the lungs alongside tumors, modulating the inflammation-associated immunosuppressive microenvironment and impeding the creation of polymorphonuclear cells.HA coating on the nanoparticles masked the excess positive charge and enabled tumor targeting through specific interactions with CD44 receptors expressed on the surface of tumor cells.The drug transport system, F I G U R E 6 (A) Gold nanorod (AuNR)-based synergistic immunotherapy and inhibition of tumor recurrence.(B) Characterization and in vitro antitumor effects.(C) Synthesis, characterization, and in vitro inhibition of aPDL1-LA.(D) Collaborative detection and suppression of postoperative tumor recurrence in vivo.(Reprinted with permission from Publisher [ref.89]) in conjunction with anti-inflammatory and chemotherapeutic interventions, effectively suppressed perioperative regeneration and lung metastasis in breast cancer 90 (Figure 7).Leng et al. developed an injectable hydrogel composed of HA, paclitaxel (PTX) nanoparticles (PPNPs), and epirubicin (EPB) (designated as PPNP/EPB@HA-Gel).In a murine perioperative mammary tumor model, PPNPs/EPB@HA-Gel exhibited controlled and sustained drug release, resulting in extended suppression of tumor recurrence and metastasis, while substantially extending the survival period without any detectable systemic toxicity.In vitro experiments demonstrated that the drugincorporated hydrogel effectively impeded tumor cell proliferation and migration.Moreover, in vivo studies revealed a notable enhancement in tumor cell apoptosis upon administration of the hydrogel.Thus, PPNPs/EPB@HA-Gel can serve as provincial chemotherapeutic agent to hinder breast cancer regeneration and metastasis F I G U R E 7 (A) The anticancer mechanism of HA@CA/DOX NPs.(B) Tumor targeting and drug release of HA@CA/DOX NPs.(C) HA@CA/DOX NPs relieved tumor immunosuppressive microenvironment.(D) HA@CA/DOX NPs significantly inhibits postoperative recurrence and lung metastasis of breast cancer.DOX, doxorubicin.(Reprinted with permission from Publisher [ref.90]) following surgery 91 (Figure 8A,B).Gu et al. developed a springy lentinan (LNT)/ chitosan (CS) cell composite (LNT/CS sponge) for extremely effective provincial transport to prevent postoperative breast cancer recurrence.The resulting sponge exhibited consistent porosity and continuous release of LNT, both in laboratory settings (in vitro) and in living organisms (in vivo).Moreover, in a mouse model of subcutaneous postoperative recurrence, the sponges reduced postoperative recurrence and suppressed long-term tumor regeneration, while exhibiting good biocompatibility.Subsequent studies showed that LNT inhib-ited the pluripotency of breast cancer cells, which could potentially account for its prolonged inhibitory effect on tumor recurrence 92 (Figure 8C,D).Liu et al. developed an injectable phase-change gel (PGE) loaded with telratolimod (Tel), a TLR7/8 agonist.In vivo investigations have revealed that Tel@PGE enhanced the recruitment of effector CD8 T lymphocytes (T cells) and promoted the polarization of MDSCs and immunosuppressive M2like macrophages into tumor-killing antigen-presenting cells.Tel@PGE-induced remodeling of the tumor microenvironment (TME) elicited a systemic immune response F I G U R E 8 (A) Preparation and action diagram of PPNPs/EPB@HA-Gel.(B) Anti-cancer effects of different formulations in vivo.(Reprinted with permission from Publisher [ref.91]) (C) Preparation and characterization of LNT/CS sponge.(D) Postoperative antitumor effect of LNT/CS sponge.EPB, epirubicin.(Reprinted with permission from Publisher [ref.92]) Zhuang et al. used in situ formation of injectable hydrogels to locally control the release of GEM and DOX to hinder prostate cancer regeneration.After mixing aldehyde hyaluronic acid (HA-CHO) and carboxymethyl chitosan (CM-CS), rapid hydrogel formation was examined by instant insertion into the postoperative cavity.Additionally, the combination of DOX with HA-CHO and GEM-doped CM-CS resulted in the formation of GEM/DOX-HA/CS-gelatin (GD-HA/CS-Gel).The drug-free hydrogel exhibited minimal cellular toxicity toward L929 cells and demonstrated favorable in vivo compatibility with living tissues.The hydrogel had suitable viscoelasticity and fast self-repairing capability, which facilitated long-period provincial residence at the injection site, with rapid release of GEM and slow release of DOX.GEM and DOX exerted synergistic anticancer effects on 4T1 cells.A xenograft model utilizing breast cancer 4T1 cells was constructed and subsequent surgical resection of the tumor was implemented.The application of the GD-HA/CS-Gel within the perioperative lumen engendered the hindrance of cancer recurrence and remote lung metastasis compared with using a single drugcarrying hydrogel or drug solution.Provincially placed dual-loaded luminal-adapted hydrogels can potentially prevent postoperative tumor recurrence95 (Figure9A,B).To mitigate the regeneration of breast cancer following surgical intervention, Chen et al. devised a new core-shell fiber scaffold that combines phase-change materials with photothermal and chemotherapeutic agents, which serve as thermal stimuli to facilitate controlled drug release, thus achieving a synergistic therapeutic impact.The scaffold was generated by synthesizing zeolite imidazolate framework-8 (ZIF-8) shells on the external surface of polybutylene succinate/lauric acid phase-change fibers (PCFs) using an in situ fabrication approach, resulting in the formation of PCF@ZIF-8.Upon optimization of the core-shell structure and phase-change features, the PCF@ZIF-8 scaffolds co-loaded with AuNRs and DOX showed notable enhancements in in vitro performance and in vivo anticancer effectiveness.In pH 7.4 of a healthy tissue microenvironment, the ZIF-8 shell allowed for a controlled and sustained delivery of DOX.Upon tumor regeneration, the acidic microenvironment induces the breakdown of the ZIF-8 shell.Upon subjecting the sample to secondary near-infrared laser irradiation, the heat generated by AuNRs directly eradicated the recurrent tumor cells and expedited the release of DOX by introducing a phase transition of lauric acid.The authors revealed welldefined, controllable reaction stimuli that offer an assuring strategy for the postoperative prevention of regeneration in cancer96 (Figure 9C,D).Sun et al. used recombinant human granulocytemacrophage colony-stimulating factor and recombinant

4. 1
.3 CRC Liu et al. devised a biomimetic nanosystem-incorporated bioscaffold to regulate the triple immune response against postoperative CRC regeneration.The shPvt1-CM-D nanosystem was constructed by encapsulating plasmids encoding short hairpin RNA against plasmacytoma variant translocation 1 (Pvt1) within liposomes, referred to as "D," revised with modified CRC CM.The nanosystem, along with the chemical agent oxaliplatin (Oxa), was contained in HA together with alginate-based bioscaffolds intended for implantation following surgery.ShPvt1-CM-D-mediated Pvt1 knockdown enhanced Oxa-induced immunogenic cell death (ICD), while augmented ICDreleased tumor antigens along with shPvt1-CM-D-released CM act as double vaccines for DCs.Knockdown of Pvt1 by shPvt1-CM-D in granulocyte MDSCs (G-MDSCs) ameliorated G-MDSC-mediated immunosuppression 101 (Figure 11A,B).Zhang et al. introduced a novel localized chemotherapy method encompassing the establishment of gene-based IONPs as a treatment for patients with postsurgical glioblastoma, targeting iron death and apoptosis to solve these issues.The permeable framework of iron oxide nanoparticles (IOPs) featuring specific carboxyl F I G U R E 1 0 (A) The mechanism of doxorubicin (DOX) and silk fibroin combined inhibition of postoperative recurrence of hepatocellular carcinoma cell (HCC).(B) Preparation and characterization of lactobionic acid-Janus nanoparticles (LA-JNPs).(C and D) Effect of LA-JNPs on postoperative recurrence of HCC.(Reprinted with permission from Publisher [ref.98])

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I G U R E 1 3 (A) Schematic illustration of the design of a biodegradable hydrogel patch.(B) Therapeutic effects of free lysine-specific demethylase 1 (iLSD1) on chemoresistant triple-negative breast cancer (TNBC).(C) Epitaxial gel for tumor-initiating cell (T-IC) differentiation and immune activation.(D) Single-dose epitaxial gel inhibits tumor recurrence and metastasis.(Reprinted with permission from Publisher [ref.115])

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I G U R E 1 5 (A) Establishment of 3D microgel.(Reprinted with permission from Publisher [ref.129]) (B) Schematic illustration depicting the fluorescent glycan nanoparticles (FGNPs)-based fluorescence-activated cell sorting (FACS) assays and their applications.(C) FACS method based on FGNP was used to diagnose drug resistance in multiple drug-resistant cancer cells.(Reprinted with permission from Publisher [ref.131]) drug resistance genes.The DR phenotype could distinguish non-DR progenies.Subsequent assessments showed that the assay could quantitatively assess the degree of drug resistance in DR cells and gauge the reversal of resistance resulting from different therapeutic interventions.This breakthrough will help to advance therapeutic diagnostics for chemotherapy resistance and cancer stemness 131 (Figure 15B,C).
Xiao: Investigation; visualization; writingoriginal draft.Lin Wang: Conceptualization; supervision; writing-review & editing.Qinglai Tang: Conceptualization; investigation; visualization.Qinglai Tang: Supervision; project administration.Xinming Yang: Supervision; project administration.Gangcai Zhu: Conceptualization; investigation.Lanjie Lei: Supervision; project administration.Shisheng Li: Supervision; project administration; funding acquisition; writing-review & editing.A C K N O W L E D G M E N T SThis work was supported by the Natural Science Foundation of Hunan Province (no.2021JJ40845) and the National Natural Science Foundation of China (no.81602389).

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ATA AVA I L A B I L I T Y S TAT E M E N T Not applicable.C O N S E N T F O R P U B L I C AT I O N Not applicable.O R C I DShisheng Li https://orcid.org/0000-0001-5874-6049RE F E R E N C E S