Checkpoint Nano‐PROTACs for Activatable Cancer Photo‐Immunotherapy

Abstract Checkpoint immunotherapy holds great potential to treat malignancies via blocking the immunosuppressive signaling pathways, which however suffers from inefficiency and off‐target adverse effects. Herein, checkpoint nano‐proteolysis targeting chimeras (nano‐PROTACs) in combination with photodynamic tumor regression and immunosuppressive protein degradation to block checkpoint signaling pathways for activatable cancer photo‐immunotherapy are reported. These nano‐PROTACs are composed of a photosensitizer (protoporphyrin IX, PpIX) and an Src homology 2 domain‐containing phosphatase 2 (SHP2)‐targeting PROTAC peptide (aPRO) via a caspase 3‐cleavable segment. aPRO is activated by the increased expression of caspase 3 in tumor cells after phototherapeutic treatment and induces targeted degradation of SHP2 via the ubiquitin‐proteasome system. The persistent depletion of SHP2 blocks the immunosuppressive checkpoint signaling pathways (CD47/SIRPα and PD‐1/PD‐L1), thus reinvigorating antitumor macrophages and T cells. Such a checkpoint PROTAC strategy synergizes immunogenic phototherapy to boost antitumor immune response. Thus, this study represents a generalized PROTAC platform to modulate immune‐related signaling pathways for improved anticancer therapy.