Bimodal disruption of the crosstalk between cancer cells and fibroblasts using nanomedicine augments cancer immunotherapy

Abstract Cancer cells program fibroblasts into a pro-tumorigenic and immunosuppressive cancer associated fibroblasts (CAFs) in a two-step manner. First, cancer cells secrete exosomes to reprogram quiescent fibroblasts into the activated CAF phenotype. Second, cancer cells maintain the CAF phenotype via activation of signal transduction pathways in the fibroblasts. We rationalized that inhibiting this two-step process can normalize the CAFs into quiescent fibroblasts and augment the efficacy of immune checkpoint inhibitors. We show that a cancer cell-targeted dual-drug combination nanomedicine that inhibits the sequential steps of exosome biogenesis and release from lung cancer cells can block the differentiation of lung fibroblasts into CAFs. In parallel, we demonstrate that a CAF-targeted dual-drug nanomedicine that blocks two distinct nodes in the FGFR-Wnt/β-catenin signal transduction pathway can reverse activated CAFs to a quiescent fibroblast state. Co-administration of both nanomedicines significantly improves the infiltration of cytotoxic T cells and enhances the antitumor efficacy of αPD-L1 antibody in an immunocompetent mice model of lung cancer. Simultaneously blocking the tumoral exosome-mediated activation of fibroblasts and FGFR-Wnt/β-catenin signaling axes may constitute a promising approach to augment immunotherapy.