The core value of surgery for advanced endometrial cancer is maximizing lesion resection through cytoreductive tumor surgery, thereby creating more favorable conditions for subsequent adjuvant therapy. The decision to pursue surgery for recurrent endometrial cancer depends primarily on whether the recurrence is local or distant/widespread. Furthermore, the extent and timing of surgery must be individualized based on the patient’s molecular subtype and the overall systemic condition.

Surgery in patients with advanced or recurrent endometrial cancer aims to achieve “no gross residual disease” (R0 resection), which is significantly associated with long-term survival (18). Traditionally, surgery for advanced or recurrent disease is performed after a thorough assessment of tumor resectability. Local recurrence is preferably managed with radical approaches, especially in patients who do not initially receive radiotherapy or whose recurrence occurs a considerable time (>12 months) after radiotherapy. The benefits of surgery are limited in patients with extensive peritoneal dissemination or distant organ metastases. Successful surgery is achieved through complete resection, with multiple studies confirming that patients with R0 resection have a significantly superior median overall survival (OS) compared to those with incomplete resection. A phase II trial involving 41 patients with stage III–IV or recurrent endometrial cancer used a “sandwich” protocol (three cycles of docetaxel + carboplatin chemotherapy → surgery → three cycles of chemotherapy + radiotherapy), and reported a 5-year OS rate of 70%; those with no gross residual disease derived even more substantial survival benefit (19). The CEEGOG EX01 trial, which included 230 patients with recurrent endometrial cancer, found that those who achieved R0 resection had a median survival of 113 months compared with 35 months for those who underwent R1/R2 resection (20). The timing of surgery is crucial. For patients with a high tumor burden, in whom direct surgery is challenging, neoadjuvant chemotherapy (NACT) can reduce lesion size and surgical risk. However, NACT may alter the molecular characteristics of tumor cells, potentially impacting subsequent choices for targeted therapy (21).

Molecular classification provides a new basis for surgical decision-making in advanced endometrial cancer. For instance, despite potentially having a high tumor burden, patients with the POLE ultramutated subtype exhibit a high sensitivity to immunotherapy. Overly aggressive surgical resection may increase the risk of complications; therefore, after confirming the molecular subtype via biopsy, prioritizing immunotherapy followed by minimally invasive surgery after tumor reduction should be considered (8). In contrast, tumors in patients with p53abn are highly aggressive. Despite achieving R0 resection, the risk of recurrence remains high, necessitating surgery and systemic chemotherapy to control micro-metastases. Patients with HER2-positive serous endometrial cancer require combined anti-HER2 therapy postoperatively (22). In patients with the MMRd subtype, tumors are highly immunogenic. Although lymph node micro-metastases are present, postoperative immunotherapy may effectively control the disease. Consequently, the scope of lymph node dissection can be appropriately reduced to minimize complications, such as lymphedema (19).However, there is currently a lack of high-level evidence from prospective clinical trials to systematically evaluate the safety and long-term efficacy of the strategy of “reducing the extent of lymphadenectomy,” and further research is still required for confirmation.

Radiotherapy is primarily used for postoperative adjuvant treatment, local lesion control, and palliative care in patients with advanced and recurrent endometrial cancer. Its value must be comprehensively evaluated based on the patient’s molecular subtype, residual surgical status, and response to systemic therapy. In patients with gross residual disease (R1/R2 resection) or positive lymph nodes, pelvic external beam radiotherapy (EBRT) combined with vaginal brachytherapy (VBT) can significantly reduce local recurrence. The PORTEC-2 study demonstrated that, for high-risk early-stage patients, the vaginal recurrence rates for VBT and EBRT were similar (2.3% vs. 1.9%, respectively); however, VBT had lower intestinal toxicity (23). This applies to advanced-stage patients, especially those with the ultra-mutated POLE or MMRd molecular subtypes whose tumors exhibit high sensitivity to radiotherapy, which can produce a synergistic effect with immunotherapy (24). MMRd tumors may undergo immunogenic cell death after radiotherapy, thereby enhancing the efficacy of subsequent immunotherapy; thus, sequential immunotherapy following radiotherapy can be considered. Conversely, p53abn tumors showed stronger resistance to radiotherapy, with local control rates from radiotherapy alone of <50%. Therefore, combining radiotherapy with chemotherapy or targeted therapy is necessary to improve its efficacy. Radiotherapy is suitable for patients with local recurrence who are ineligible for or who refuse surgery. Brachytherapy alone can achieve a 5-year local control rate of approximately 70% for vaginal cuff recurrence. For pelvic lymph node recurrence, EBRT combined with chemotherapy (cisplatin sensitization) can increase the local control rate to 60–70% (25, 26). Recently, the use of stereotactic body radiotherapy (SBRT) for oligometastases has gradually increased. Its advantages include a short treatment course (1–5 sessions), minimal damage to normal tissues, and local control rates >80% (27).

Systemic therapy serves as the cornerstone of the management of advanced and recurrent endometrial cancer. Chemotherapy forms the backbone, and platinum-based regimens remain a fundamental choice. The rapid development of targeted therapies and immunotherapies has revolutionized the treatment of advanced and recurrent diseases. Particularly, precision medicine guided by molecular classification significantly improves patient outcomes. However, clonal evolution and spatiotemporal heterogeneity of tumors pose major challenges to precision therapy. Differences in molecular subtypes can exist between primary and recurrent tumors and within different regions of the primary tumor itself. One study involving 141 patients with recurrence found subtype conversion in four cases (3.8%), in which two shifted from MMRd to p53abn and two from p53wt to p53abn, suggesting that recurrent lesions may acquire new molecular alterations (28). The clinical implication of this dynamic molecular evolution is that re-evaluation of the molecular profile upon recurrence may alter the treatment strategy.

The efficacy of immunotherapy is suboptimal in patients with pMMR-type disease, making the elucidation of resistance mechanisms a core challenge in current research. Existing studies indicate that immunotherapy resistance can be categorized into primary and acquired resistance involving multiple factors, such as tumor cell-intrinsic factors, abnormalities in the immune microenvironment, and host factors. At the tumor cell level, common causes of resistance include loss of HLA molecule expression, defects in the antigen presentation machinery, aberrations in the IFN-γ signaling pathway, and downregulation of PD-L1 expression (60, 61). Aberrant remodeling of the immune microenvironment is significant in immunotherapy resistance. Immunosuppressive cells within the tumor microenvironment, such as regulatory T cells, myeloid-derived suppressor cells, immune checkpoint molecules, and metabolic reprogramming, collectively form immunosuppressive barriers that impede the infiltration and function of effector T cells (60, 61). Furthermore, the physical barrier formed by extracellular matrix components secreted by cancer-associated fibroblasts further restricts the depth of immune cell infiltration (62). Therefore, combination strategies, such as combining immune checkpoint inhibitors with antiangiogenic agents, chemotherapy, or radiotherapy, aim to remodel the immune microenvironment and enhance the immune response.

Combination strategies for overcoming resistance to immunotherapy are continuously being developed. Combined chemotherapy and immunotherapy has become the first-line standard of care for patients with advanced endometrial cancer. Previously, the RUBY trial demonstrated that this combination significantly prolonged PFS in patients with dMMR. Similarly, the NRG GY018 study is a phase II clinical study designed to evaluate the efficacy and safety of three targeted combination regimens—pembrolizumab plus lenvatinib, pembrolizumab plus olaparib, and lenvatinib plus olaparib—in patients with advanced or recurrent endometrial cancer who have received at least one prior line of platinum-based chemotherapy, showed that pembrolizumab combined with carboplatin/paclitaxel significantly extended PFS compared to chemotherapy alone, regardless of the MMR status (63, 64). Building on the findings of KEYNOTE-775, the NRG GY018 trial not only corroborated the efficacy of the pembrolizumab-plus-lenvatinib regimen in the second-line setting but also explored novel combination strategies involving PARP inhibitors paired with either immunotherapy or anti-angiogenic therapy. These explorations provide a new therapeutic avenue for patients with homologous recombination deficiency (HRD)-positive tumors. Furthermore, the differential efficacy observed among the three distinct combination regimens underscores the necessity of biomarker-guided selection to identify the optimal treatment strategy for individual patients (65).The combination of dual immune checkpoint inhibitors further improves response rates and duration of response in patients with dMMR. Although dostarlimab monotherapy achieved an ORR of 49% in dMMR advanced endometrial cancer, combining it with a CTLA-4 inhibitor may further enhance its efficacy (47, 66). Additionally, a combination of immunotherapy and PARP inhibitors (as observed in the DUO-E study) demonstrated synergistic effects in advanced endometrial cancer, particularly in HRD-positive patients, providing a rationale for exploring “chemotherapy-free” regimens (58, 63). The development of novel immunotherapeutic agents has provided new tools to combat drug resistance. Besides traditional PD-1/PD-L1 inhibitors, clinical trials are evaluating new immune checkpoint inhibitors, T-cell agonists, and bispecific antibodies. The CD276-targeted bispecific antibody CC-3, which simultaneously binds to CD276 on tumor cells and CD3 on T cells, recruits T cells to the tumor site and activates their killing function, demonstrating potent cytotoxicity against endometrial cancer cell lines in vitro (67). Furthermore, clinical trials of adoptive cell therapies targeting tumor-specific antigens (e.g., NY-ESO-1) are underway and offer potential treatment options for advanced treatment-resistant patients (Figure 3).