Reprogramming the Tumor Mechanical Microenvironment with Lactate Inhibition and Stimulator of Interferon Genes Activation to Potentiate Systematic Radio-Immunotherapy

Biomechanics shape tissue and cellular behavior, with altered mechanical cues driving tumor progression, immune escape, and therapy resistance. However, strategies to fully understand and remodel the tumor mechanical microenvironment (TMM) with antitumor immunity and metabolism for therapeutic gain are still evolving and unclear. Here, we design a multifunctional nanomusketeer to reprogram the TMM by simultaneous lactate regulation and stimulator of interferon genes (STING) pathway activation to elucidate their interplay and enhance radio-immunotherapy. Specifically, the engineered nanomusketeer could significantly activate the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) STING pathway and reduce lactate levels by 50% compared to PBS controls. More importantly, unlike conventional radiotherapy, which can disrupt the cytoskeleton but promote extracellular matrix (ECM) remodeling that fuels radioresistance, the nanomusketeer dramatically downregulates these structural components, softening tumors, increasing permeability, and enhancing effector T cell infiltration. This synergistic effect markedly improves radio-immunotherapy efficacy against both primary and distant tumors, manifesting potential clinical applications of TMM reprogramming.