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Two CAF subtypes exhibit immunomodulatory properties via different mechanisms. mCAFs sythesize extracellular matrix and may restrict T cell invasion in low-grade tumors via ensheathing tumor nests, while iCAFs are enriched in late-stage tumors, and express high levels of cytokines and chemokines to aid immune cell recruitment and activation. This is supported by the induction of an iCAF-like phenotype with immunomodulatory functions in primary healthy fibroblasts exposed to skin cancer cell secretomes. Thus, targeting CAF variants holds promise to enhance immunotherapy efficacy in skin cancers.</jats:p>","journal":"Nature Communications","year":2024,"id":639786,"datarank":1.6137538280523431,"base_score":4.672828834461906,"endowment":4.672828834461906,"self_citation_contribution":0.7009243251692859,"citation_network_contribution":0.9128295028830573,"self_endowment_contribution":0.7009243251692859,"citer_contribution":0.9128295028830573,"corpus_percentile":null,"corpus_rank":null,"citation_count":106,"citer_count":103,"citers_with_citation_signal":71,"citers_with_endowment":71,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1662500,"name":"Bertram Aschenbrenner","orcid":"0000-0003-1177-7109","position":1,"is_corresponding":false},{"id":1493991,"name":"Ana Korosec","orcid":"0000-0001-6551-6727","position":2,"is_corresponding":false},{"id":1022900,"name":"Tina Jacob","orcid":"0000-0002-7180-2698","position":3,"is_corresponding":false},{"id":805797,"name":"Karl Annusver","orcid":"0000-0002-9515-7216","position":4,"is_corresponding":false},{"id":1662509,"name":"Natalia Krajic","orcid":"0000-0002-9255-5251","position":5,"is_corresponding":false},{"id":1662511,"name":"Daria Kholodniuk","orcid":null,"position":6,"is_corresponding":false},{"id":1662513,"name":"Sophie Frech","orcid":"0000-0002-6190-8595","position":7,"is_corresponding":false},{"id":1662516,"name":"Shaohua Zhu","orcid":null,"position":8,"is_corresponding":false},{"id":804253,"name":"Kim Purkhauser","orcid":"0000-0003-1732-9673","position":9,"is_corresponding":false},{"id":1662518,"name":"Katharina Lipp","orcid":null,"position":10,"is_corresponding":false},{"id":815053,"name":"Franziska Werner","orcid":"0000-0002-1502-2259","position":11,"is_corresponding":false},{"id":503534,"name":"Vy Nguyen","orcid":"0000-0003-1553-0912","position":12,"is_corresponding":false},{"id":79929,"name":"Johannes Griss","orcid":"0000-0003-2206-9511","position":13,"is_corresponding":false},{"id":642758,"name":"Wolfgang Bauer","orcid":"0000-0002-1063-3237","position":14,"is_corresponding":false},{"id":1662521,"name":"Ana Soler Cardona","orcid":null,"position":15,"is_corresponding":false},{"id":1652954,"name":"Benedikt Weber","orcid":"0000-0002-7217-4590","position":16,"is_corresponding":false},{"id":605595,"name":"Wolfgang Weninger","orcid":"0000-0003-3133-8699","position":17,"is_corresponding":false},{"id":1662523,"name":"Bernhard Gesslbauer","orcid":null,"position":18,"is_corresponding":false},{"id":1662525,"name":"Clement Staud","orcid":null,"position":19,"is_corresponding":false},{"id":1662527,"name":"Jakob Nedomansky","orcid":null,"position":20,"is_corresponding":false},{"id":1662529,"name":"Christine Radtke","orcid":null,"position":21,"is_corresponding":false},{"id":953908,"name":"Stephan N. 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This study dissects the intra-tumoral diversity of CAFs in basal cell carcinoma, squamous cell carcinoma, and melanoma using molecular and spatial single-cell analysis. We identify three distinct CAF subtypes: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs), and immunomodulatory CAFs (iCAFs). Large-cohort tissue analysis reveals significant shifts in CAF subtype patterns with increasing malignancy. Two CAF subtypes exhibit immunomodulatory properties via different mechanisms. mCAFs sythesize extracellular matrix and may restrict T cell invasion in low-grade tumors via ensheathing tumor nests, while iCAFs are enriched in late-stage tumors, and express high levels of cytokines and chemokines to aid immune cell recruitment and activation. This is supported by the induction of an iCAF-like phenotype with immunomodulatory functions in primary healthy fibroblasts exposed to skin cancer cell secretomes. 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