Metabolic reprogramming in cancer-associated fibroblasts: orchestrating the tumor immune microenvironment and response to immune checkpoint blockade.

Abstract

Immune checkpoint blockade (ICB) has reshaped the therapeutic landscape of solid tumors. However, durable clinical benefit remains limited to a subset of patients because of primary or acquired resistance. Beyond tumor-intrinsic factors, the tumor microenvironment (TME) plays a critical role in shaping responsiveness to immunotherapy. As a major stromal component, cancer-associated fibroblasts (CAFs) contribute to immune suppression through dynamic metabolic reprogramming and modulate the spatial organization and functional state of immune cells. Recent advances in single-cell transcriptomics, spatial omics, and metabolomic profiling have provided new insights into the metabolic heterogeneity of CAF subsets and their interactions with immune cells. Metabolic reprogramming not only sustains CAF activation but also remodels the local immune environment through nutrient competition, metabolite accumulation, and coordination with extracellular matrix remodeling. These processes reinforce immunosuppression within the TME and contribute to resistance to ICB. This review integrates emerging multi-omics insights into CAF metabolic heterogeneity, summarizes how metabolic reprogramming shapes tumor immunity, and discusses therapeutic strategies targeting CAF metabolism to enhance immunotherapy efficacy, together with the major challenges facing clinical translation.