Cytokine-mediated intrinsic and extrinsic regulation of anti-tumor adoptive T cell therapy.

Adoptive T cell therapy has transformed the treatment of hematologic malignancies but fails to control solid tumors, where T cell dysfunction and an immunosuppressive tumor microenvironment (TME) remain the central barriers. Cytokines are essential regulators of both T cell fate and the TME, making cytokine engineering a key lever for overcoming these limitations. Here we review recent advances in intrinsic strategies that embed cytokine support directly into the engineered T cell product and extrinsic strategies that deliver cytokines to the tumor site to remodel the TME, providing a comprehensive analysis to guide rational strategy selection and combination. We further highlight synthetic cytokine and receptor designs that induce novel T cell states beyond the boundaries of natural T cell biology. Finally, we propose virtual cytokine networks as a framework for predicting patient-specific immune cascades triggered by any designed cytokine intervention, providing a path toward personalized cytokine-guided adoptive T cell therapy.