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Background Stem-like progenitor exhausted T cells (T ) provide long-term resistance against chronic viral infections and cancer, and are an important target for functional reinvigoration by PD-1 checkpoint blockade immunotherapy (CBI). A better understanding of mechanisms that drive the development of CBI -responsive stem-like exhausted T cells, and regulate their differentiation into functional effector cells are critical for commandeering improved immunotherapeutic outcomes.Methods We evaluated de novo designed cytokine mimetics for their ability to modulate CAR-T cell fate and enhance the therapeutic efficacy of CAR-T cell and checkpoint blockade combination therapies against refractory solid tumors in immunocompetent preclinical models through their effects on anti-tumor function and TME.Results Our studies show a crucial fate-deterministic role of tempered IL-2 signals during the initial priming and activation phase in programming TCF-1Hi stem-like precursor T cells, which are durable and respond to anti-PD-1 therapy in later stages of exhaustion. In the context of human tumors as well, scRNA-seq analyses of antigen-specific tumor infiltrating lymphocytes from melanoma, head and neck cancer and lung cancer patients show an inverse relationship of IL-2 signaling signature with stemness of exhausted T cells, as well as checkpoint blockade therapy outcomes. Notably, regulated IL-2 signals during CAR-T cell product manufacturing also promoted the development of long-lived, stem-like TCF-1 cells, capable of synergy with PD-1 CBI for enhanced solid tumor control. Thus contrasting the well-established role of strong IL-2 signals through IL-2Ra in vigorous effector cytotoxic T lymphocyte (CTL) differentiation during PD-1 CBI at later stages of chronic disease, these studies highlight a distinctive role of tempered IL-2 signaling through the IL-2Rb/g heterodimer in programming the long-lived, PD-1 therapy responsive stem-like lineage during the initial priming phase. Our studies further show that de novo designed mimetics of another common gamma-chain family cytokine, IL-21, also enhance solid tumor control through dual effects on effector CTL differentiation, and by converting the TME to immunologically hot phenotype.Conclusions These finding bear relevance to improving immunotherapy outcomes for a broad range of adult and pediatric solid tumors including neuroblastoma, glioma, melanoma and sarcoma.Acknowledgements This work was supported by research funding from the Pediatric Cancer Research Foundation to SS, the Rachel Lynn Henley Foundation to VK, the Hopes and Smiles For Children Foundation to VK, In Concert for Cancer Foundation to VK and the National Institutes of Health (CA254168 to TP; CA225517 to PN; AI132819, AI103748 to SS; 5P30CA015704; AI154363 to VK).