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 MnO₂ 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, Mn²⁺, and vaccine protein (CCV). LOX will catalyze the lactate oxidation to generate H₂O₂ and exacerbate hypoxia, thereby simultaneously activating Mn²⁺-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 Mn²⁺ 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.