Hypoxia-responsive immunostimulatory nanomedicines synergize with checkpoint blockade immunotherapy for potentiating cancer immunotherapy.

• The CS combination induced an enhanced immunogenic cellular response. • Hypoxia-degradable CS@TAP nanoparticles for initiating tumor immunotherapy. • CS@TAP nanoparticles reversed the tumor immunosuppressive microenvironment. • The combination of CS@TAP and αPD-L1 significantly improved the therapeutic effect. Inducing cell death while simultaneously enhancing antitumor immune responses is a promising therapeutic approach for multiple cancers. Celastrol (Cel) and 7-ethyl-10-hydroxycamptothecin (SN38) have contrasting physicochemical properties, but strong synergy in immunogenic cell death induction and anticancer activity. Herein, a hypoxia-sensitive nanosystem (CS@TAP) was designed to demonstrate effective immunotherapy for colorectal cancer by systemic delivery of an immunostimulatory chemotherapeutic combination. Furthermore, the combination of CS@TAP with anti-PD-L1 mAb (αPD-L1) exhibited a significant therapeutic benefit of delaying tumor growth and increased local doses of immunogenic signaling and T -cell infiltration, ultimately extending survival. We conclude that CS@TAP is an effective inducer of immunogenic cell death (ICD) in cancer immunotherapy. Therefore, this study provides an encouraging strategy to synergistically induce immunogenic cell death to enhance tumor cytotoxic T lymphocytes (CTLs) infiltration for anticancer immunotherapy. [ABSTRACT FROM AUTHOR]