Endometrial cancer is the most common gynecologic malignancy in developed countries, and its incidence continues to climb, in part tracking rising obesity and aging populations. Early-stage disease is often cured with surgery, with or without adjuvant radiotherapy, but options for advanced, recurrent, or metastatic cases remain limited. The treatment landscape has shifted dramatically in recent years: immune checkpoint blockade targeting PD-1 or PD-L1 has moved from a niche option in recurrent mismatch repair-deficient disease into first-line combination with platinum-taxane chemotherapy for primary advanced or recurrent tumors, with checkpoint inhibition continued after chemotherapy ends. Benefit is strongest in mismatch repair-deficient tumors but is clinically meaningful even in proficient mismatch repair disease, meaning mismatch repair status alone does not fully explain who responds.

This is precisely where fibroblasts enter the picture. If stromal cells help build an immune-excluded tumor microenvironment, they could plausibly contribute to incomplete response, primary resistance during chemo-immunotherapy, persistence of immune-excluded residual disease during continuation immunotherapy, or progression after prior checkpoint inhibitor exposure. But the review is emphatic that plausibility is not proof. Direct evidence linking fibroblast programs to clinical checkpoint-inhibitor resistance in endometrial cancer remains limited, and most available studies support stromal immune modulation rather than a demonstrated causal effect on immunotherapy response.

The strongest endometrial cancer-specific findings involve tumor promotion rather than immune escape. Endometrial cancer-derived fibroblasts have been shown to induce epithelial-mesenchymal transition and drive tumor-cell growth, including through IL-6/STAT3/c-Myc signaling. Fibroblast-derived SDF-1/CXCL12 has been implicated in tumor-cell proliferation, migration, and invasion through the CXCR4 receptor. CD146-positive fibroblasts have been functionally shown to promote angiogenesis and vasculogenic mimicry through IL-10/JAK1/STAT3 signaling. Tumor-cell-derived SPARC can activate fibroblasts in a fibronectin-dependent manner. On the immune side, the key direct experiment comes from a co-culture study in which endometrial cancer-derived fibroblasts suppressed natural killer cell activity in healthy donor cells, with reduced fibroblast surface PVR/CD155 implicated, although the consequences for actual tumor-cell killing and treatment response were not established.

Single-cell and spatial transcriptomic studies have added resolution but also cautionary lessons. One single-cell RNA sequencing study of human endometrial cancer divided fibroblasts into four clusters: matrix, inflammatory, vascular, and antigen-presenting cancer-associated fibroblasts. Another study of endometrioid endometrial carcinoma identified myofibroblast, pericyte, MKI67-positive, WNT-niche-related, and BMP-positive stromal populations. However, these clusters came from limited patient cohorts, and the antigen-presenting cluster in particular was small and dominated by a single tumor sample. The review argues these should be treated as transcriptionally defined, emerging stromal states rather than an established, reproducible taxonomy. The influential myofibroblastic versus inflammatory fibroblast framework was originally built in pancreatic cancer, and functional equivalence across tumor types cannot simply be assumed.

Many of the most compelling immune-evasion mechanisms come from other malignancies entirely. In pancreatic cancer mouse models, CXCR4 blockade promoted T-cell accumulation and cooperated with anti-PD-L1 treatment, providing a therapeutic hypothesis for endometrial cancer but no demonstration of CXCL12-dependent T-cell sequestration in this disease. In ovarian cancer, CAF-S1 fibroblast populations enriched in mesenchymal tumors have been associated with CXCL12β-mediated immunosuppression and regulatory T-cell accumulation. In gastric cancer, a 2025 study showed that FAP knockdown reduced PD-L1 expression on cancer-derived fibroblasts and enhanced CD8 T-cell effector molecules including granzyme B, TNF-α, and interferon-γ in co-culture. In non-endometrial models of cholangiocarcinoma, pancreatic, breast, and pancreatic ductal adenocarcinoma cancers, mean tumor stiffness correlated inversely with T-cell velocity and displacement, and pharmacological inhibition of lysyl oxidase reduced stiffness and improved T-cell displacement in all four models, with velocity gains only in one. These are correlations and cross-cancer experiments, not endometrial cancer findings.

On the therapeutic front, the review sorts candidate strategies by translational maturity, and none has established clinical efficacy or validated patient-selection utility in endometrial cancer. FAP-directed approaches, including monoclonal antibodies, CAR-T cells, vaccines, and radioligands, have reached early-phase clinical testing in other solid tumors, such as phase I evaluation of locally delivered FAP-targeted CAR-T cells in malignant pleural mesothelioma and phase I/II radioligand trials in advanced solid tumors, but these were not conducted in endometrial cancer. TGF-β pathway inhibition has substantial clinical history, including a randomized phase III study of the bifunctional TGF-β/PD-L1 agent bintrafusp alfa in PD-L1-high non-small cell lung cancer that failed to beat pembrolizumab and carried higher rates of severe adverse events. The CXCR4 antagonist motixafortide has been tested with pembrolizumab and chemotherapy in phase II pancreatic cancer work. Matrix-directed therapy has been humbling: the anti-LOXL2 antibody simtuzumab did not improve outcomes in a randomized phase II study of metastatic pancreatic cancer.

Stromal reprogramming offers a different philosophy: rather than killing fibroblasts, alter their state. A proof of principle came from pancreatic ductal adenocarcinoma models, where activation of vitamin D receptor signaling with calcipotriol shifted cancer-associated pancreatic stellate cells toward a less activated state and modified their paracrine effects on tumor-cell transcriptional programs. For endometrial cancer, this remains a preclinical concept requiring confirmation of vitamin D receptor expression and responsiveness in relevant fibroblast populations. IL-6/JAK/STAT3 targeting has direct disease-specific mechanistic rationale from the tumor-growth experiments, but the pleiotropic role of this pathway across tumor, immune, and stromal compartments limits specificity, and circulating IL-6 cannot be assumed to reflect fibroblast activity.

The review also flags serious barriers to translation. Fibroblasts are heterogeneous, and some populations may restrain tumors or support antitumor immunity, so indiscriminate depletion could backfire. Common markers such as FAP, α-SMA, PDGFRβ, and vimentin lack the specificity needed to identify pathogenic subsets or select patients. Safety is a genuine concern because fibroblasts maintain tissue homeostasis, wound healing, and repair, raising the possibility of impaired healing or aberrant fibrosis after systemic stromal targeting, a consideration particularly relevant in a disease where surgery is frequent. Candidate biomarkers such as CD146, periostin, and CXCL12- or IL-6-associated programs are exploratory research tools, and no fibroblast-derived signature has been prospectively validated as a predictor of response to current checkpoint-based combinations in endometrial cancer.

The bottom line is a disciplined research agenda rather than a clinical recommendation. Current evidence supports selected fibroblast-mediated tumor-promoting activities and one fibroblast-immune interaction, altered natural killer cell activity, in endometrial cancer, while direct functional evidence for T-cell exclusion, dendritic-cell dysfunction, myeloid reprogramming, matrix-dependent immune resistance, and checkpoint resistance remains limited and largely borrowed from other cancers. The authors call for validating fibroblast-immune mechanisms in endometrial cancer specifically, developing reproducible stromal biomarkers, and testing treatment combinations in disease-specific models and clinical studies, including longitudinal cohorts with paired pre-treatment and post-progression samples to determine whether fibroblast evolution actually drives acquired immunotherapy resistance. Until those links are established, findings from pancreatic, breast, gastric, and other tumors should be read as mechanistic precedents and hypotheses, not as established features of endometrial cancer biology.

Subject of Research: Cancer-associated fibroblasts, immune evasion, and therapeutic targeting in endometrial cancer

Article Title: Cancer-associated fibroblasts and immune evasion in endometrial cancer: current evidence and therapeutic perspectives

Article References: Zhan, J., Yan, Z., Cao, Z., Wu, F., Wang, Y., & Zhan, Y. (2026). Cancer-associated fibroblasts and immune evasion in endometrial cancer: current evidence and therapeutic perspectives. Medical Oncology, 43(11), Article 355. https://doi.org/10.1007/s12032-026-03471-8

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03471-8

Keywords: endometrial cancer, cancer-associated fibroblasts, tumor microenvironment, immune evasion, immunotherapy resistance, immune checkpoint inhibitors, TGF-beta, CXCL12-CXCR4, IL-6 STAT3, FAP, stromal reprogramming, tumor stiffness