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IL-12 signaling synergized with CAR activation to sustain mTORC1 activity through convergent Ras-ERK and PI3K pathways, promoting metabolic fitness, autonomous expansion, and sustained effector function. IL-12 also activated bystander NK cells, T cells, and macrophages to remodel the tumor microenvironment. To improve safety, IL-12 was tethered to a collagen-binding A3-domain, restricting its activity to the extracellular matrix and limiting systemic exposure. In ovarian and pancreatic cancer models, matrix-anchored IL-12 CAR NK cells expanded without exogenous cytokines and achieved durable tumor control. These findings suggest that mTORC1-mediated integration of CAR and cytokine signaling can enhance immune fitness and overcome immunosuppressive tumor microenvironments.<\/jats:p>","DOI":"10.1158\/2159-8290.cd-26-0509","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:17:42Z","timestamp":1790723862000},"update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatially confined IL-12 programs CAR-NK through mTORC1 to coordinate antitumor immune networks"],"prefix":"10.1158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4440-1565","authenticated-orcid":false,"given":"Mubin","family":"Tarannum","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 2 Boston, MA","place":["United 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