Targeting Tumor–CAFs Crosstalk to Reverse Drug Resistance and Immunosuppression Through Cuproptosis

ABSTRACT Chemotherapy resistance and immunosuppression are the current key bottlenecks in tumor treatment. In the tumor microenvironment (TME), cancer‐associated fibroblasts (CAFs) secrete dense extracellular matrix and various immunosuppressive factors, forming a dynamic “tumor–CAFs crosstalk”, which drives the progression of resistance and evasion. During the formation of resistance, CAFs remodel the “pre‐resistance microenvironment” through upregulation of chemokines, providing support for tumors to acquire the resistant phenotype. Consequently, the study has constructed a dual‐targeted nanoplatform D/CM‐HI that combines interference with tumor‐CAFs crosstalk and reversal of resistance. This system achieves combined regulation of tumors and CAFs through dual receptor targeting of CD44 and FAP, blocking the formation of the resistance microenvironment. Mechanistically, D/CM‐HI exerts dual reprogramming effects: it inhibits CAFs activation, reduces TGF‐β secretion, and weakens the hypo‐responsiveness and immunosuppressive phenotype driven by CXCL12; concurrently, it induces tumor cell cuproptosis, downregulates resistance factors such as HIF‐1α, MDR, and P‐gp, reshaping the resistance microenvironment at the metabolic and transport levels. In the tumor‐CAFs co‐culture system, D/CM‐HI significantly interferes with the FAP–TGF‐β–CXCL12 signaling axis and reduces the resistance of tumors. Thus, D/CM‐HI achieves dual reprogramming of tumor–CAFs crosstalk and the resistant microenvironment to additively overcome resistance and immunosuppression.