Reversing hypoxia-induced immune evasion in tumors to enhance cancer immunotherapy

The strategy of inducing tumors to release damage-associated molecular patterns (DAMPs) to trigger immunogenic cell death has garnered significant attention in cancer therapy. However, the hypoxic tumor microenvironment, which is often programmed by cancer cells, results in the release of immunosuppressive DAMPs (iDAMPs), which substantially influence antitumor immune responses. In this study, we developed a redox-responsive carboxymethyl chitosan (CMC)-based nanoplatform for the sequential delivery of a hypoxia-inducible factor 1-α (HIF-1α) inhibitor, 3-(5'-hydroxymethyl-2-furyl)-1-benzylindazole (YC-1), and the chemotherapeutic agent doxorubicin (DOX), aimed to restore therapeutic sensitization and immunostimulation in tumors. The preferential release of YC-1 effectively targets the HIF-1α/cyclooxygenase-2 (COX-2) axis, significantly reducing the secretion of immunosuppressive factor prostaglandin E₂ (PGE₂), thereby resensitizing tumors to Tcell-mediated immunity. Additionally, YC-1 mitigates hypoxia-induced tumor chemoresistance by inhibiting the HIF-1α/P-glycoprotein (P-gp) axis, further improving the immunotherapeutic efficacy of DOX. Our work demonstrates that regulating hypoxia-induced immunosuppressive factors in tumors contributes to the inhibition of both primary and metastatic tumors, offering a promising approach to enhance immunotherapies.