Potentiating Chemo‐Immunotherapy via a Programmable Nanocapsule‐Hydrogel Platform for Sequential Tumor Microenvironment Remodeling

Abstract

ABSTRACT Durable responses to cancer immunotherapy require both robust antitumor immunity and sustained immune pressure within the immunosuppressive tumor microenvironment (TME). Chemotherapeutics can induce transient immune priming and modulate TME features but are limited by unpredictable immune response durations and systemic toxicity when combined with immunotherapy. To overcome these challenges, we develop a programmable delivery platform integrating chemotherapeutics and immune checkpoint blockade within a silk fibroin hydrogel containing pH‐responsive nanocapsules for controlled temporal release at tumor sites. Leveraging molecular weight differences, the small chemotherapeutic oxaliplatin rapidly diffuses to initiate tumor‐intrinsic immunogenic stress, while the larger anti‐PD‐L1 nanocapsules undergo gradual degradation in the TME, enabling sustained checkpoint engagement. This strategy converts non‐immunogenic tumor cells into a heightened immunogenic state, modulates key immune features of the TME, and supports durable antitumor responses and long‐term central memory T cell persistence in a murine breast tumor model. Our findings demonstrate that this multifunctional platform, combining chemotherapy‐induced immunogenic stress with controlled checkpoint blockade, offers a generalizable approach for designing next‐generation chemo‐immunotherapy combinations in cancer treatment.