Targeting FGFR signaling overcomes therapeutic resistance and immune evasion in oncogenic PIK3CA-driven serous-like endometrial cancer

We developed the first clinically relevant, immunocompetent SEC mouse model incorporating PIK3CA mutation, TP53 loss, and MYC overexpression. Through comprehensive analysis integrating mouse models, human cell lines, xenografts, and clinical samples, we investigated mechanisms of PIK3CA-targeted therapy resistance. Single-cell transcriptional profiling identified FGFR1/2 association with intrinsic resistance and FGFR3 with acquired resistance. Dual inhibition of FGFR and PI3Ka achieved enhanced tumor suppression. Additionally, we discovered that FGFR signaling promotes immune evasion by downregulating MHC-I/HLA-mediated antigen processing and presentation. Importantly, FGFR inhibition not only reversed immune suppression by restoring antigen presentation but also demonstrated a synergistic effect with anti-PD-1 therapy, enhancing immunotherapy response and anti-tumor immune memory. Our findings reveal FGFR's dual role in therapy resistance and immune evasion, supporting FGFR inhibition as a promising strategy to enhance treatment outcome in SEC patients.