Tumor‐Targeting Co‐Delivery of T‐Cell Antigen and Camptothecin Guided by Cascade‐Responsive Peptide Self‐Assembly to Reshape Tumor Antigenicity for Cancer Immunotherapy

Abstract Antigen presentation deficiency restricted by class I major histocompatibility complex (MHC‐I) causes low antigenicity and antigen escape in tumors, thereby limiting T‐cell immunotherapy outcomes. Here, a combined tumor immunotherapy is developed, in which tumors can present exogenous non‐tumor antigens, and adoptively transferred CD8 + T cells specific for these antigens are re‐targeted to attack tumors. The approach leverages a cascade‐responsive peptide self‐assembly to co‐deliver suitable antigens and the chemotherapeutic drug camptothecin (CPT) to tumors. As a proof‐of‐concept, to re‐target ovalbumin (OVA)‐specific OT‐I CD8 + T cells against tumors, PSA (Nap‐GFFpYE‐ss‐Ag) and CPSA (CPT‐GFFpYE‐ss‐Ag) are constructed, containing an OVA‐derived epitope OVA 257‐264 and/or CPT. The design enables the release of a unique N‐terminal extended OVA 257‐264 and CPT into the cytosol. As a result, the extended antigen is efficiently presented on the tumor surface by MHC‐I, and CPT further enhances this presentation. When combined with adoptively transferred OT‐I CD8 + T cells, the approach effectively facilitates CD8 + T cell infiltration and tumor inhibition. Additionally, CPSA treatment sensitizes immune responses to programmed cell death‐ligand 1 (PD‐L1) blockade, allowing the approach to synergize with an anti‐PD‐L1 antibody for improved tumor eradication.