Dual regulation of metabolism and immune contact by a self-reinforcing hydrogel enhances CAR-T-mediated residual tumor clearance and surveillance.

CAR-T therapy holds immense potential for eradicating residual tumors and restoring postoperative immune surveillance. However, nutrient deprivation and impaired immune contact within the postoperative tumor microenvironment (PTME) severely hinder the therapeutic efficacy of CAR-T cells. Herein, we developed a self-reinforcing hydrogel system that dually modulated metabolism and immune contact to reprogram the PTME. Specifically, the c-Myc inhibitor JQ1 and bovine serum albumin (BSA)-decorated nanoparticles loaded with the actin cytoskeleton inhibitor NP-G2-044 (BPG) were encapsulated into a reactive oxygen species (ROS)-sensitive hydrogel (JQ1 + BPG@gel). Upon implantation into the surgical cavity, JQ1 + BPG@gel underwent ROS-responsive degradation, continuously releasing agents. JQ1 not only suppressed glycolysis in tumor cells, thereby redirecting nutrients toward CAR-T cells and alleviating lactic acid-induced immunosuppression, but also upregulated the gradients of chemokines CCL5 and CXCL10, thus providing a strong driving force for CAR-T cell infiltration. Notably, JQ1-induced glycolysis inhibition significantly enhanced the tumor uptake of BSA, establishing a self-reinforcing internalization process for BPG. The increased intracellular accumulation of BPG remodeled actin cytoskeleton, enhancing the spatial co-localization between T cells and tumor cells while reducing the steric hindrance imposed by complex cellular topology, thereby facilitating the formation of immune contact and tumor lysis. This hydrogel system improved the anti-recurrence efficacy of CAR-T therapy by 9-fold compared with monotherapy while establishing durable immune surveillance via memory T-cell differentiation within lymphoid organs. This research offers an innovative strategy to improve postoperative tumor cure rates and potentiate CAR-T immunotherapy.