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While most approved cell therapies are T cell\u2010based, this limitation motivates the exploration of an alternative effector cell platform. Natural killer (NK) cells, innate cytotoxic lymphocytes capable of antigen\u2010independent recognition and killing, offer a compelling foundation for next\u2010generation therapies with an improved safety profile. In this review, we first outline the cellular, molecular, and metabolic features of the immunosuppressive TME that restrict cytotoxic lymphocyte function, emphasizing mechanisms that limit immune cell\u2010mediated responses. We then summarize key aspects of NK cell biology that can circumvent these barriers and critically evaluate current NK\u2010based strategies, including engineered chimeric antigen receptor (CAR)\u2010NK products and metabolic and trafficking interventions. Finally, we highlight emerging in vivo viral and mRNA\/lipid nanoparticle platforms for CAR\u2010NK generation and their potential to enhance scalability and therapeutic durability.<\/jats:p>","DOI":"10.1002\/advs.75326","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T10:58:08Z","timestamp":1776769088000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Reprogramming Antitumor Immunity: NK Cell Strategies to Navigate the Immunosuppressive Tumor Microenvironment"],"prefix":"10.1002","volume":"13","author":[{"given":"Tereza","family":"Kochs","sequence":"first","affiliation":[{"name":"Medical Oncology Department Dana\u2010Farber Cancer Institute Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pranay","family":"Nath","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Dana\u2010Farber Cancer 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