Fibroblast‐Activation Protein Targeted Immunostimulant to Provoke Colorectal Cancer Immunity Through Photodynamic Depleting and Chemotherapeutic Silencing of Cancer Associated Fibroblasts

Abstract Colorectal cancer cells are capable of reprogramming normal fibroblasts into tumor‐supportive cancer‐associated fibroblasts (CAFs), whose immunosuppressive crosstalk profoundly hinders antitumor immune responses. In this work, a significant association between CAF activation and disease‐free survival outcomes is established in colorectal cancer patients. Complementary biological investigations confirm the interactive dynamics between fibroblasts and colorectal cancer cells that drive CAF activation. Based on these, a fibroblast‐activation protein (FAP)‐targeted immunostimulant (called PDC) is fabricated to provoke colorectal cancer immunity through spatiotemporal regulation of CAFs. The PDC system can selectively deliver vitamin D receptor (VDR) agonist calcipotriol (Cal) and photosensitizer protoporphyrin IX (PpIX) into CAFs via the FAP‐specific peptide. Subsequently, PpIX ablates CAFs directly through photodynamic therapy (PDT) to mitigate their immunosuppressive characteristics, while Cal reprograms the activated CAFs into a quiescent state for persistent immune regulation. Additionally, the robust PDT induces immunogenic cell death of colorectal cancer and triggers subsequent immunological cascades. Pathophysiological and immunological assessments demonstrate that PDC not only remodels the collagen matrix and inhibits primary tumor growth, but also recruits and activates cytotoxic T lymphocytes (CTLs) to suppress lung metastases. This approach provides a complementary strategy for the spatiotemporal regulation of CAFs, offering a novel avenue for colorectal cancer immunotherapy.