The Role of Distinct Cancer-Associated Fibroblast Subtypes in Prostate Cancer Immunotherapy

Abstract

Immune checkpoint inhibitors (ICIs) have achieved breakthroughs in various solid tumors; however, their efficacy remains limited in prostate cancer (PCa), which is closely associated with its highly immunosuppressive tumor microenvironment (TME). As the most abundant stromal component in the TME, cancer-associated fibroblasts (CAFs) exhibit remarkable heterogeneity and functional plasticity, playing a central role in orchestrating an immunologically "cold" tumor phenotype and driving resistance to immunotherapy. We have moved beyond simple marker-based classification of cancer-associated fibroblast (CAF) subtypes — a framework still widely used in routine pathological assessment — and now define these populations by their functional states and molecular profiles, enabled by advances in single-cell sequencing, spatial multi-omics, and computational biology. Such functional divergence across stromal subsets allows individual CAF populations to engage in complex, multilayered crosstalk with different immune cell types, and together they build an immunosuppressive network that drives tumor immune evasion. This review systematically catalogs the identification methods and signature gene panels for distinct CAF subtypes in prostate cancer, with particular focus on the multilayered regulatory circuits through which these stromal cells shape the immune microenvironment. We also highlight emerging CAF-targeted strategies designed to reverse immunosuppressive states. This integrated perspective frames CAF heterogeneity in prostate cancer immune evasion, and establishes theoretical underpinnings and translational pathways for next-generation precision combination immunotherapies.