Trichosanthin Fused to Thermo-pH-Sensitive Polypeptides for Synergistic Cancer Immunotherapy

Immunogenic cell death (ICD) induced in cancer chemotherapy, radiotherapy, and photodynamic therapy can facilitate the maturation of dendritic cells (DCs) and the activation, proliferation, and tumor infiltration of cytotoxic T lymphocytes, which may synergize with immune checkpoint blockade (ICB) therapy to improve therapeutic outcomes. Herein, we report a novel ICD inducer of TCS-ELP(HI), in which a multifunctional biologic of trichosanthin (TCS) is genetically fused to a thermo-pH-sensitive elastin-like polypeptide (ELP(HI)). This fusion offers a thermo-pH-sensitive property to TCS, leading to not only the formation of a sustained-released depot of TCS-ELP(HI) upon intratumoral injection but also the enhanced tumor cell uptake and lysosomal escape of TCS-ELP(HI) as compared to free TCS. As a result, TCS-ELP(HI) shows increased tumor penetration as well as improved tumor retention as compared to TCS alone, resulting in enhanced antitumor efficacy and boosted ICD. The combination of TCS-ELP(HI) with an immune checkpoint inhibitor leads to enhanced therapeutic efficacy in treating primary and distant tumors due to the synergy of ICD and ICB in antitumor immunity. These results indicate that TCS-ELP(HI) is promising as a new ICD inducer to synergize with an immune checkpoint inhibitor to improve antitumor and antimetastasis efficacy.