REMODELING THE TUMOR MICROENVIRONMENT: INTRATUMORAL PIRFENIDONE SENSITIZES MURINE TUMORS TO ANTI-PD-1 THERAPY

Abstract

The tumor microenvironment (TME) represents a critical barrier to effective cancer immunotherapy. Pirfenidone (PFD), an anti-fibrotic agent, has shown promise in modulating the immunosuppressive TME by inhibiting the TGF-β pathway. Objective: To evaluate the antitumor efficacy of intra-tumoral pirfenidone (PFD), an anti-fibrotic agent with tumor microenvironment (TME)-modulating properties, alone and in combination with anti-PD-1 antibody therapy in syngeneic CT26 colon carcinoma and 4T1 breast cancer models. Methods: CT26 colon carcinoma and 4T1 breast cancer-bearing mice were treated with intra-tumoral pirfenidone either as monotherapy or in combination with anti-PD-1 antibodies. Tumor growth was monitored throughout the study. Results: Pirfenidone monotherapy attenuated tumor growth in both CT26 and 4T1 tumor models. Combination treatment with pirfenidone and anti-PD-1 antibodies resulted in significantly greater tumor growth inhibition compared with monotherapy. Furthermore, tumors from the combination-treated group exhibited enhanced antitumor immune responses and favorable remodeling of the tumor microenvironment. These findings suggest that pirfenidone-mediated TME remodeling enhances the efficacy of checkpoint inhibitors and warrants further investigation as a combination immunotherapy strategy.