{"doi":"10.1016/j.canlet.2024.217319","title":"Engraftment of a surrogate antigen onto tumor cell surface via pHLIP peptide to universally target CAR-T cell therapy to solid tumors","abstract":"CAR-T cells and monoclonal antibodies (mAbs) are immunotherapeutics that have shown efficacies against certain malignancies. However, their broad application is hindered by the scarcity of tumor-associated antigens on tumor cell surfaces. Previous investigations unveiled the unique capacity of pH-low insertion peptide (pHLIP) to anchor to plasma membranes under acidic conditions. Considering that an acidic tumor microenvironment is a hallmark of solid tumors, we engineered a novel peptide, Myc-pHLIP, by tethering a surrogate epitope tag, the c-Myc-tag, to pHLIP. We evaluated the efficiency of Myc-pHLIP in inserting the artificial c-Myc-tag onto the plasma membrane of malignant cells and determined if this engraftment could convert it into a therapeutic target for CAR-T cells or mAbs. Our in vitro experiments demonstrated that incubating Myc-pHLIP with tumor cells in acidic media triggered significant killing by either Myc-targeted CAR-T cells (Myc-CAR-T), or by an anti-Myc mAb in the presence of NK cells. In vivo studies demonstrated substantial antitumor effects with sequential administration of Myc-pHLIP followed by either Myc-CAR-T or Myc-mAb. These findings establish that Myc-pHLIP has the potential to act as a universal surrogate tumor antigen capable of directing CAR-T cells or mAbs to treat any solid tumors by concurrently targeting both malignant and stromal cells. • CAR-T cell and antibody therapy have shown efficacies against certain malignancies. • The paucity of suitable tumor-associated antigens hampers their clinical application. • A hallmark of solid tumors is the acidic tumor microenvironment. • Tethering a surrogate epitope, the c-Myc-tag, to low pH membrane-inserting peptide (pHLIP) can overcome the lack of tumor antigen targets. • This c-Myc-Tag-pHLIP peptide allows tumor cells to be recognized and killed by both CAR-T and antibody therapy.","journal":"Cancer Letters","year":2024,"id":472311,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":796581,"name":"Xinping Fu","orcid":null,"position":1,"is_corresponding":false},{"id":1307775,"name":"Jane Jing Ting Lim","orcid":null,"position":2,"is_corresponding":false},{"id":690256,"name":"Shaun Xiaoliu Zhang","orcid":null,"position":3,"is_corresponding":false},{"id":1053108,"name":"Yanting Zhang","orcid":"0000-0001-8647-9021","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T02:05:53.032464Z","pmid":"39489212","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}