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A highly fibrotic, immunosuppressive microenvironment poses a significant barrier to effective immunotherapy. As key innate immune effectors of antitumor immunity, the functional status of natural killer (NK) cells within this environment remains poorly understood. This study aims to explore the role of stromal\u2013immune interactions, particularly myofibroblastic cancer-associated fibroblasts (myCAFs) and NK cells, in shaping immune dysfunction in PDAC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated spatial, single-cell and bulk transcriptomic analyses to characterize NK-cell heterogeneity and its cellular and molecular regulation in PDAC. CellChat-based communication analysis, spatial co-localization, and multiplex immunofluorescence were utilized to identify regulatory interactions and validate spatial associations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A tumor-associated NK (TaNK) subset with impaired cytotoxicity was identified. myCAFs strongly interacted with TaNK cells through collagen signaling. Within ligand\u2013receptor pairs, COL1A2\u2013CD44 and COL1A1\u2013LAIR1 served as dominant mediators linking stromal remodeling to impaired NK cell function. Spatial and histological validation confirmed their co-localization, while tumors co-enriched with myCAFs and TaNKs exhibited immune exclusion and poor response to immunotherapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study demonstrates that collagen signaling from myCAFs impairs NK-cell cytotoxicity and promotes immune exclusion in PDAC. These findings advance the understanding of stromal\u2013immune mechanisms underlying immunotherapy resistance and highlight that targeting the myCAF\u2013NK axis may help improve the response to immunotherapy in PDAC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08237-4","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T15:05:49Z","timestamp":1779462349000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multimodal transcriptomics reveal myCAF-derived collagen signaling associated with impaired NK-cell cytotoxicity and immune exclusion in pancreatic cancer"],"prefix":"10.1186","volume":"24","author":[{"given":"Lei","family":"Kong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengxin","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1097-6942","authenticated-orcid":false,"given":"Jun","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"issue":"1","key":"8237_CR1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3322\/caac.21763","volume":"73","author":"RL Siegel","year":"2023","unstructured":"Siegel RL, Miller KD, Wagle NS, Jemal A. 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