Stromal APOL4 defines a cancer-associated fibroblast state that organizes a chemosensitive niche in ovarian cancer

Abstract Despite initial high response rates to platinum-based chemotherapy in high-grade serous ovarian carcinoma, most patients eventually develop resistance, and the contribution of the tumor microenvironment to treatment outcomes has remained underexplored relative to tumor cell-intrinsic mechanisms. Combining patient-derived ex vivo carboplatin screening with bulk and single-cell transcriptomics, functional perturbation in cancer-associated fibroblasts (CAFs), and high-resolution spatial transcriptomics, we identified stromal apolipoprotein L4 (APOL4) as a biomarker of platinum sensitivity. The ex vivo classification showed directional concordance with clinical platinum response, and stromal APOL4 expression predicted favorable outcomes across multiple validation cohorts. APOL4 specifically marked a transcriptionally distinct CAF subtype (CAF-1) that extended beyond canonical CAF states and exhibited high matrix metalloproteinase and immune-activating cytokine expression. APOL4 knockdown attenuated the CAF-1 transcriptional program, and in 3D tumor–CAF co-cultures conferred carboplatin resistance to 12 of 14 ovarian cancer cell lines, providing causal evidence that stromal APOL4 supports platinum sensitivity in a tumor cell-extrinsic manner. NicheNet analysis revealed bidirectionally asymmetric communication: CAF-1 engaged non-stressed cancer cells through epithelial integrity-supporting axes, whereas other CAFs preferentially reinforced stressed, drug-tolerant cancer cells through canonical chemoresistance circuits. High-resolution Xenium spatial transcriptomics revealed a contact-restricted spatial association between CAF-1 proximity and reduced cancer-cell stress, defining a low-stress, immune-infiltrated niche that is spatially and compositionally distinct from the stress-enriched, immune-poor niche associated with CAF-2, with CAF-3 sharing features of both compartments. These findings identify stromal APOL4–CAF-1 as a prognostic biomarker and a functional contributor linking stromal matrix remodeling to platinum sensitivity and associated with an immune-infiltrated microenvironment, highlighting CAF-1-targeted strategies to enhance chemotherapy efficacy.