Spatiotemporally reprogrammed L-arginine metabolic nanoregulator potentiates immunotherapy

L-arginine (L-Arg) deprivation in the tumor microenvironment (TME) drives effector T cell dysfunction and immunotherapy resistance. However, simply supplementing L-Arg can be counterproductive, as tumor cells and immunosuppressive myeloid cells act as dominant consumers, co-opting the nutrient to promote tumor progression. To break this detrimental cycle without fueling protumoral networks, we develop a near-infrared (NIR)-triggered nanoregulator (hPFL@Lipo) to simultaneously alleviate intratumoral L-Arg deficiency and redirect its metabolism to support antitumor immunity. This nanoregulator was constructed through coordination-driven self-assembly to co-load and stabilize L-Arg and Fe 3+ within hollow Prussian blue (hPB) nanoparticles, followed by lipid membrane encapsulation for enhanced systemic stability. Under NIR irradiation, hPFL@Lipo releases Fe 3+ and L-Arg while generating localized hyperthermia. Fe 3+ repolarizes M2-like macrophages toward an M1 phenotype, thereby increasing the intratumoral M1-to-M2 ratio. The photothermal effect induces immunogenic tumor cell death, which promotes the infiltration of cytotoxic CD8 + T cells. Concurrently, the released L-Arg supplements the local pool, while thermal ablation reduces the overall cellular burden within the tumor, thereby alleviating arginine local depletion. Together, this strategy resolves the tumor–immune conflict over L-Arg by remodeling the intratumoral landscape of L-Arg consumers in favor of antitumor effector cells, thereby reprogramming the net metabolism of the tumor from a tumor-promoting to a tumor-suppressing state and achieving potent synergy with αPD-1 therapy. • hPFL@Lipo alleviates intratumoral L-arginine depletion upon near-infrared (NIR) irradiation. • hPFL@Lipo reprograms the tumor immune landscape by repolarizing M2 macrophages and enhancing CD8 + T cell infiltration. • hPFL@Lipo reconfigures intratumoral nutrient competition to favor antitumor immunity. • The nanoregulator synergizes potently with immune checkpoint inhibitors to enhance antitumor efficacy.