Targeting stromal FAK signaling to address chemotherapy and immunotherapy resistance in gastric-type endocervical adenocarcinoma.

Abstract

5524 Background: Gastric-type endocervical adenocarcinoma (GAC) is a rare, HPV-independent cervical cancer subtype with profound resistance to standard chemotherapy and radiotherapy and an exceptionally poor prognosis. Unlike HPV-associated cervical cancers, GAC lacks established molecular targets and effective treatment strategies. Whether patients with GAC can benefit from immunotherapy remains unclear, and the biological mechanisms underlying its intrinsic resistance to both cytotoxic and immune-based therapies are poorly understood. Methods: We established an integrated translational platform incorporating patient-derived GAC cell lines, organoids, and matched primary cancer-associated fibroblasts (CAFs). These models were integrated with multi-omics profiling of clinical specimens, including single-cell RNA sequencing of 58 cervical lesions across disease states, together with molecular and functional validation assays, to systematically characterize tumor–stroma interactions and identify actionable therapeutic vulnerabilities. Results: Multi-omics analyses revealed that GAC converges on a pancreatic ductal adenocarcinoma–like transcriptional and microenvironmental program characterized by stromal dominance and therapeutic refractoriness. Mechanistically, GAC tumor cells reprogram the tumor microenvironment through secretion of LAMA3, activating a CD44/ITGB1-dependent FAK signaling axis in CAFs. Stromal FAK activation drives extracellular matrix remodeling and endothelial dysfunction, establishing a profoundly immunosuppressive niche marked by impaired antigen presentation and enrichment of tissue-resident CD8 + T cells (CD8 + ITGA1 + ). This stromal program mechanistically underlies resistance to both chemotherapy and immunotherapy. In patient-derived GAC organoid-based models, FAK inhibition enhanced responses to chemotherapy and immunotherapy in vitro, supporting a translational rationale for FAK-targeted combination strategies. Based on these findings, we initiated a multicenter, phase II clinical trial evaluating the FAK inhibitor IN10018 in combination with nab-paclitaxel and cadonilimab in patients with metastatic, recurrent, or persistent GAC (NCT06654011). Conclusions: Gastric-type endocervical adenocarcinoma is a stroma-driven malignancy in which aberrant stromal FAK signaling is a central mediator of resistance to both chemotherapy and immunotherapy. Targeting this stromal dependency provides a compelling therapeutic strategy and directly informs an ongoing phase II clinical trial addressing a critical unmet need in this aggressive disease.