Abstract Cancer‐associated fibroblasts (CAFs) play a pivotal role in the metabolic symbiosis that drives tumor proliferation and immune evasion. Paradoxically, eliminating CAFs can disrupt tissue homeostasis and potentially accelerate tumor spread. To address this challenge, this study proposes a novel strategy to reprogram CAFs, transforming them into “anchors” and “fuel stations” for anti‐tumor immune cells, thereby enhancing the immune response against tumors. Utilizing a fibroblast‐specific lipid nanoparticle (LNP) delivery system, key metabolic genes in CAFs are targeted and downregulated, specifically hexokinase 2 (HK2) and mitochondrial cytochrome c oxidase I (MTCO1). The dual inhibition of glycolysis and mitochondrial respiration in CAFs consequently results in glucose overload and mitochondrial dysfunction. As a result, these energy‐deprived CAFs exhibit high expression of MHC II molecules and inflammatory cytokines, promoting immune cell infiltration and providing essential fuel for subsequent activation and proliferation. Furthermore, this metabolic reprogramming results in reduced angiogenesis and an immune microenvironment characterized by M1 macrophage polarization and enhanced lymphocyte infiltration. Consequently, this approach improves the efficacy of immune checkpoint inhibitors (ICIs) in castration‐resistant prostate cancer (CRPC). Thus, the reprogramming of CAFs into immune cell allies offers a promising strategy to overcome the limitations of current ICIs therapies.

Metabolic Reprogramming of Cancer‐Associated Fibroblasts: Transforming Tumor Accomplices into Immunotherapeutic Allies