{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T06:52:30Z","timestamp":1781679150728,"version":"3.54.5"},"reference-count":179,"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. Immunol."],"abstract":"<jats:p>Adoptive T cell therapies have markedly improved outcomes in hematologic malignancies but their efficacy in solid tumors can be diminished by a hostile tumor microenvironment that impedes sustained therapeutic responses. Beyond challenges such as limited trafficking and antigen heterogeneity, engineered T cells face suppressive myeloid and stromal populations, inhibitory checkpoint ligand interactions, and metabolically hostile niches that collectively diminish effector function and persistence. To overcome these barriers, a new generation of fusion protein-based costimulatory strategies has emerged that couple ligand-guided sensing of the tumor microenvironment with modular control of T cell activation and fate. This review examines how conventional and non-canonical costimulatory modules, when incorporated into chimeric antigen receptor (CAR) and T cell receptor (TCR) architectures, modulate T cell differentiation and function within the tumor site. It further analyzes how membrane-anchored and secreted fusion proteins enable engineered T cells to activate dendritic cells, reprogram myeloid cells, and convert poorly inflamed tumors into treatment-responsive environments. Together, these advances establish a design framework in which fusion protein\u2013based receptors and ligands enhance T cell function and remodel the tumor microenvironment, thereby expanding the therapeutic potential of adoptive T cell therapy for solid tumors.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1819470","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T05:56:05Z","timestamp":1781675765000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Fusion protein-mediated costimulation in engineered T cells: from intrinsic signaling to tumor microenvironment rewiring"],"prefix":"10.3389","volume":"17","author":[{"given":"Ryma","family":"Toumi","sequence":"first","affiliation":[{"name":"Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children\u2019s Research Institute","place":["Seattle, WA, United 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