Gradient Zinc-Doping Strategy Combined With Tumor Metabolic Interference for Effective Catalytic Immunotherapy.

Abstract

Photocatalytic immunotherapy has attracted significant attention due to high selectivity and low side effects. However, the poor tissue penetration of ultraviolet-visible light and the low energy of near-infrared (NIR) photons, combined with the immunosuppressive tumor microenvironment (TME), severely limit catalytic efficiency and immune activation. In this study, we designed a gradient Zn² ⁺-doping polymeric carbon nitride (PCN) nanocatalyst (gZn-PCN@M), in which the Zn² ⁺ concentration gradually decreases from the interior to the surface of the PCN nanosheets. Under 808 nm laser irradiation, gZn-PCN@M catalyzes the decomposition of H₂O in tumor interstitial fluid to produce hydrogen gas, which reduces the intratumoral delivery resistance, markedly enhancing the penetration depth of gZn-PCN into tumors. Meanwhile, the acidic TME and laser irradiation further promote Zn² ⁺ release from gZn-PCN, resulting in abnormally elevated intracellular Zn² ⁺ levels that triggers ROS bursts and disrupts tumor energy metabolism, thereby downregulating PD-L1 expression in tumor cells and activating antitumor immune responses. The results indicated that the inhibition rates of gZn-PCN on primary tumors and distant tumors were 96.51% and 83.69%, respectively. This study proposes a gradient ion-doping strategy for the first time to enhance the NIR responsiveness of photocatalytic nanomedicines, combined with metabolic interference to achieve efficient tumor photocatalytic immunotherapy.