VaccineIntegrated Nanoplatform for Lactate‐Activatable Chemo/Chemodynamic Therapy and Multiple Immune Regulations of Tumor

Abstract Enhancing the synergistic effect of chemo‐immunotherapy remains a major challenge in the field of cancer treatment. Besides, the premature release of chemotherapeutic or immunotherapeutic agents usually causes systemic immune disorders, leading to the weakness of immunotherapy. Here, a vaccine‐integrated hollow MnO 2 nanoplatform (TMLV), co‐loaded with tirapazamine (TPZ) and lactate oxidase (LOX), is developed to orchestrate lactate‐activatable multiple immune regulations against tumor. Upon accumulation in tumor, TMLV will be degraded by intracellular GSH to release its payloads: TPZ, LOX, Mn 2+ , and vaccine protein (CCV). LOX will catalyze the lactate oxidation to generate H 2 O 2 and exacerbate hypoxia, thereby simultaneously activating Mn 2+ ‐mediated chemodynamic therapy and TPZ‐involved chemotherapy. This process induces a massive release of tumor antigens while circumventing immune damage caused by premature drug release. Subsequently, CCV and Mn 2+ synergistically promote antigen presentation by stimulating Toll‐like receptor signaling and cGAS‐STING pathways in antigen‐presenting cells (APCs), respectively. The activation of cGAS‐STING pathway will further promote the cross‐presentation between activated APCs and CD8 + T cells, significantly strengthening the adaptive immunity. This adjuvant‐free design enabling multi‐pathway immune activation might offer a novel strategy to overcome key challenges in antitumor immunotherapy.