{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T22:57:36Z","timestamp":1792364256194,"version":"4.4.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Immune checkpoint blockade (ICB) has reshaped cancer therapy, yet many solid tumors remain immune-excluded, with cytotoxic T cells trapped in stromal regions and unable to access malignant nests. In these settings, cancer-associated fibroblasts (CAFs) and their extracellular matrix programs act as active ecosystem regulators that impose physical transport barriers, chemokine \u201cgating\u201d (notably CXCL12\u2013CXCR4), and stromal exclusion signals such as TGF-\u03b2, collectively sustaining resistance to both immunotherapy and targeted agents, and contributing to treatment intolerance and rehabilitation-relevant functional burden. Building on this mechanistic blueprint, we review clinically relevant strategies that use fibroblast activation protein (FAP), when sufficiently expressed and spatially relevant, as a tractable stromal address label to rewire resistant niches, ranging from FAP-targeted immunocytokines and conditional costimulation to regional FAP-CAR-T approaches and FAPI-PET\u2013enabled stratification\/theranostics. We highlight key safety constraints and failure modes that can limit not only efficacy but also functional recovery, and propose a trial-ready roadmap centered on state-guided selection, mechanism-matched combinations, early pharmacodynamic verification of rewiring, and pragmatic functional endpoints.<\/jats:p>","DOI":"10.3389\/fphar.2026.1812674","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T05:56:19Z","timestamp":1781675779000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting FAP\/CAFs to rewire immune-excluded and resistant tumor niches"],"prefix":"10.3389","volume":"17","author":[{"given":"Yingying","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Rehabilitation, Qingdao Municipal Hospital","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, Qingdao Municipal Hospital","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ce","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, Qingdao Municipal Hospital","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, Qingdao Municipal Hospital","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"A092","DOI":"10.1158\/1535-7163.targ-17-a092","article-title":"Abstract A092: Phase 1 trial of RO6874813, a novel bispecific FAP-DR5 antibody, in patients with solid tumors","volume":"17","author":"Bendell","year":"2018","journal-title":"Mol. 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