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Herein, checkpoint nano\u2010proteolysis targeting chimeras (nano\u2010PROTACs) in combination with photodynamic tumor regression and immunosuppressive protein degradation to block checkpoint signaling pathways for activatable cancer photo\u2010immunotherapy are reported. These nano\u2010PROTACs are composed of a photosensitizer (protoporphyrin IX, PpIX) and an Src homology 2 domain\u2010containing phosphatase 2 (SHP2)\u2010targeting PROTAC peptide (aPRO) via a caspase 3\u2010cleavable 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\u2010proteasome system. The persistent depletion of SHP2 blocks the immunosuppressive checkpoint signaling pathways (CD47\/SIRP\u03b1 and PD\u20101\/PD\u2010L1), 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\u2010related signaling pathways for improved anticancer therapy.<\/jats:p>","DOI":"10.1002\/adma.202208553","type":"journal-article","created":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T18:55:45Z","timestamp":1669402545000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":117,"title":["Checkpoint Nano\u2010PROTACs for Activatable Cancer Photo\u2010Immunotherapy"],"prefix":"10.1002","volume":"35","author":[{"given":"Chi","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Chemistry Chemical Engineering and Biotechnology Nanyang Technological University  70 Nanyang Drive Singapore 637457 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengke","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Chemistry Chemical Engineering and Biotechnology Nanyang Technological University  70 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