{"doi":"10.1042/bst20221083","title":"Emerging roles for tumor stroma in antigen presentation and anti-cancer immunity","abstract":"Advances in immunotherapy in the last decade have revolutionized treatment paradigms across multiple cancer diagnoses. However, only a minority of patients derive durable benefit and progress with traditional approaches, such as cancer vaccines, remains unsatisfactory. A key to overcoming these barriers resides with a deeper understanding of tumor antigen presentation and the complex and dynamic heterogeneity of tumor-infiltrating antigen-presenting cells (APCs). Reminiscent of the 'second touch' hypothesis proposed by Klaus Ley for CD4+ T cell differentiation, the acquisition of full effector potential by lymph node- primed CD8+ T cells requires a second round of co-stimulation at the site where the antigen originated, i.e. the tumor bed. The tumor stroma holds a prime role in this process by hosting specialized APC niches, apparently distinct from tertiary lymphoid structures, that support second antigenic touch encounters and CD8+ T cell effector proliferation and differentiation. We propose that APC within second-touch niches become licensed for co-stimulation through stromal-derived instructive signals emulating embryonic or wound-healing provisional matrix remodeling. These immunostimulatory roles of stroma contrast with its widely accepted view as a physical and functional 'immune barrier'. Stromal control of antigen presentation makes evolutionary sense as the host stroma-tumor interface constitutes the prime line of homeostatic 'defense' against the emerging tumor. In this review, we outline how stroma-derived signals and cells regulate tumor antigen presentation and T-cell effector differentiation in the tumor bed. The re-definition of tumor stroma as immune rheostat rather than as inflexible immune barrier harbors significant untapped therapeutic opportunity.","journal":"Biochemical Society Transactions","year":2023,"id":353358,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"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":1099616,"name":"Yun Huang","orcid":"0000-0001-6963-3728","position":1,"is_corresponding":false},{"id":336012,"name":"Alexander Cicala","orcid":"0000-0003-1424-3524","position":2,"is_corresponding":false},{"id":774341,"name":"Yaling Dou","orcid":null,"position":3,"is_corresponding":false},{"id":1099617,"name":"Matteo Fields","orcid":"0000-0002-2002-227X","position":4,"is_corresponding":false},{"id":1099618,"name":"Alicia Gibbons","orcid":"0000-0003-0567-375X","position":5,"is_corresponding":false},{"id":1100086,"name":"Duncan Hong","orcid":null,"position":6,"is_corresponding":false},{"id":1087067,"name":"Daniel J. Lagal","orcid":null,"position":7,"is_corresponding":false},{"id":331397,"name":"Victoria Quintana","orcid":"0000-0001-7178-1535","position":8,"is_corresponding":false},{"id":1100087,"name":"Alejandro Rizo","orcid":null,"position":9,"is_corresponding":false},{"id":1100088,"name":"Brolyn Zomalan","orcid":null,"position":10,"is_corresponding":false},{"id":336014,"name":"Fotis Asimakopoulos","orcid":"0000-0002-5099-1696","position":11,"is_corresponding":false},{"id":338039,"name":"Athanasios Papadas","orcid":null,"position":0,"is_corresponding":true}],"reference_count":115,"raw_metadata":null,"created_at":"2026-07-19T01:12:58.542950Z","pmid":"38031753","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":[]}