Self-reinforcing immunometabolic microneedles enable circuit-level lactate reprogramming to enhance solid tumor...

Excessive lactate accumulation in solid tumors disrupts metabolic-immune coordination within the tumor microenvironment, driving acidosis, immune suppression, and resistance to immunotherapy. Current lactate-targeting strategies mainly act on isolated metabolic nodes and therefore fail to restore coordinated control over lactate production, intracellular utilization, and extracellular immunosuppression. Here, we develop a self-reinforcing immunometabolic microneedle platform (LZH/PC MNs) to reconstruct the tumor lactate regulatory circuit at multiple levels. Calcium carbonate-mineralized photosynthetic cyanobacteria and lactate oxidase-loaded zeolitic imidazolate framework nanoparticles (LZH NPs) are hierarchically integrated into dissolvable microneedles for localized intratumoral delivery. In the acidic tumor microenvironment, calcium carbonate consumes protons to alleviate extracellular acidosis while replenishing calcium ions. Following cellular internalization, LZH NPs catalyze intracellular lactate oxidation to generate oxidative stress, thereby sustaining calcium overload and inducing immunogenic cell death. Meanwhile, light-driven photosynthetic oxygenation enhances lactate oxidase activity, destabilizes hypoxia-inducible factor 1α, suppresses glycolysis-driven lactate production, and promotes macrophage repolarization. Through the integrated regulation of extracellular acidosis alleviation, intracellular lactate depletion, and upstream metabolic inhibition, LZH/PC MNs restore lactate homeostasis, rewire tumor metabolic-immune crosstalk, and elicit systemic antitumor immunity against both primary and distant tumors. This work establishes tumor lactate metabolism as a circuit-level immunometabolic target and provides a generalizable strategy for overcoming lactate-driven immune resistance in solid tumors.