The concept of immunogenic cell death (ICD) induced by chemotherapy as a potential synergistic modality for cancer immunotherapy has been widely discussed. Unfortunately, most chemotherapeutic agents failed to dictate effective ICD responses due to their defects in inducing potent ICD signaling. Here, we report a dual-enzyme-instructed peptide self-assembly platform of CPMC (CPT-GFFpY-PLGVRK-Caps) that cooperatively utilizes camptothecin (CPT) and capsaicin (Caps) to promote ICD and engage systemic adaptive immunity for tumor rejection. Although CPT and Caps respectively prevent tumor progression by inhibiting type-I DNA topoisomerase and activating transient receptor potential cation channel subfamily V member 1 (TRPV1) for intracellular calcium overload, neither alone effectively stimulates sufficient ICD signaling to meet immunotherapeutic needs. CPMC, sequentially allowing an active Caps derivative of VRK-Caps and CPT to release extracellularly and intracellularly, can synergize two distinct apoptosis pathways stimulated by Caps and CPT to increase tumor immunogenicity and elicit systemic T-cell-based immunity. Consequently, CPMC facilitates the generation of improved tumor-specific cytotoxic T-cell responses and sustained immunological memory, successfully suppressing both primary and distant tumors. Moreover, CPMC can render tumors susceptible to PD-L1 blockade and synergize with an antiprogrammed cell death-ligand 1 (aPDL1) antibody for tumor inhibition. Combining two cancer chemotherapeutic drugs with low ICD-stimulating capacity using a peptide self-assembly strategy was demonstrated to boost ICD responses and potentiate cancer immunotherapy.

Dual-Enzyme-Instructed Peptide Self-Assembly to Boost Immunogenic Cell Death by Coordinating Intracellular Calcium Overload and Chemotherapy