Improved Efficacy of Triple-Negative Breast Cancer Immunotherapy via Hydrogel-Based Co-Delivery of CAR-T Cells and Mitophagy Agonist.

Leaky and structurally abnormal blood vessels and increased pressure in the tumor interstitium reduce the infiltration of CAR-T cells in solid tumors, including triple-negative breast cancer (TNBC). Furthermore, high burden of tumor cells may cause reduction of infiltrating CAR-T cells and their functional exhaustion. In this study, various effector-to-target (E:T) ratio experiments are established to model the treatment using CAR-T cells in leukemia (high E:T ratio) and solid tumor (low E:T ratio). It is found that the antitumor immune response is decreased in solid tumors with low E:T ratio. Furthermore, single cell sequencing is performed to investigate the functional exhaustion at a low ratio. It is revealed that the inhibition of mitophagy-mediated mitochondrial dysfunction diminished the antitumor efficacy of CAR-T-cell therapy. The mitophagy agonist BC1618 is screened via AI-deep learning and cytokine detection, in vivo and in vitro studies revealed that BC1618 significantly strengthened the antitumor response of CAR-T cells via improving mitophagy. Here, injection hydrogels are engineered for the controlled co-delivery of CAR-T cells and BC1618 that improves the treatment of TNBC. Local delivery of hydrogels creates an inflammatory and mitophagy-enhanced microenvironment at the tumor site, which stimulates the CAR-T cells proliferation, provides antitumor ability persistently, and improves the effect of treatment.