{"doi":"10.1158/2159-8290.cd-22-1125","title":"Addressing Tumor Heterogeneity by Sensitizing Resistant Cancer Cells to T cell–Secreted Cytokines","abstract":"Tumor heterogeneity is a major barrier to cancer therapy, including immunotherapy. Activated T cells can efficiently kill tumor cells following recognition of MHC class I (MHC-I)-bound peptides, but this selection pressure favors outgrowth of MHC-I-deficient tumor cells. We performed a genome-scale screen to discover alternative pathways for T cell-mediated killing of MHC-I-deficient tumor cells. Autophagy and TNF signaling emerged as top pathways, and inactivation of Rnf31 (TNF signaling) and Atg5 (autophagy) sensitized MHC-I-deficient tumor cells to apoptosis by T cell-derived cytokines. Mechanistic studies demonstrated that inhibition of autophagy amplified proapoptotic effects of cytokines in tumor cells. Antigens from apoptotic MHC-I-deficient tumor cells were efficiently cross-presented by dendritic cells, resulting in heightened tumor infiltration by IFNγ-and TNFα-producing T cells. Tumors with a substantial population of MHC-I-deficient cancer cells could be controlled by T cells when both pathways were targeted using genetic or pharmacologic approaches. SIGNIFICANCE: Tumor heterogeneity is a major barrier to immunotherapy. We show that MHC-I-deficient tumor cells are forced into apoptosis by T cell-derived cytokines when TNF signaling and autophagy pathways are targeted. This approach enables T cell-mediated elimination of tumors with a substantial population of resistant, MHC-I-deficient tumor cells. This article is highlighted in the In This Issue feature, p. 1027.","journal":"Cancer Discovery","year":2023,"id":334345,"datarank":0.4636563680037475,"base_score":3.091042453358316,"endowment":3.091042453358316,"self_citation_contribution":0.4636563680037475,"citation_network_contribution":0.0,"self_endowment_contribution":0.4636563680037475,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":271020,"name":"Deng Pan","orcid":"0000-0002-6475-0463","position":1,"is_corresponding":false},{"id":30772,"name":"Wubing Zhang","orcid":"0000-0003-2233-299X","position":2,"is_corresponding":false},{"id":845680,"name":"Xixi Zhang","orcid":"0000-0002-0944-2214","position":3,"is_corresponding":false},{"id":1062732,"name":"Tiffany Y. Juan","orcid":"0000-0003-3119-9158","position":4,"is_corresponding":false},{"id":25333,"name":"Jason W. Pyrdol","orcid":"0000-0001-7726-4192","position":5,"is_corresponding":false},{"id":277289,"name":"Oleksandr Kyrysyuk","orcid":"0000-0002-7646-6363","position":6,"is_corresponding":false},{"id":54229,"name":"John G. Doench","orcid":"0000-0002-3707-9889","position":7,"is_corresponding":false},{"id":671,"name":"X. Shirley Liu","orcid":"0000-0003-4736-7339","position":8,"is_corresponding":false},{"id":24148,"name":"Kai W. Wucherpfennig","orcid":"0000-0002-1829-302X","position":9,"is_corresponding":false},{"id":30763,"name":"Yoshinaga Ito","orcid":"0000-0002-5567-7014","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:09:48.843291Z","pmid":"36811466","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":[]}