Stem-like T cells in cancer immunotherapy: biology, regulation and therapeutic targeting

The identification of stem-like CD8⁺ T cells, also termed progenitor or precursor of exhausted T cells (T_PEX), has reshaped our understanding of durable antitumor immunity. These cells exhibit progenitor-like properties, including self-renewal capacity and multilineage differentiation potential, giving rise to both effector-like and terminally exhausted CD8⁺ T cell subsets. Accordingly, the abundance of stem-like CD8⁺ T cells correlate strongly with improved clinical outcomes in patients receiving immune checkpoint inhibitors, adoptive cell therapy, or cancer vaccines across multiple tumor types. This review synthesizes recent advances in T_PEX cells biology, highlighting interconnected research pillars, including: specialized niche microenvironments that sustain stemness of T_PEX cells through coordinated chemokine signaling and antigen-presenting cell interactions; core molecular circuitry that dynamically balances self-renewal versus effector differentiation via transcription factors and cytokines; and therapeutic reprogramming strategies that harness T_PEX cells as the primary driver of immunotherapy efficacy. Further, we explore strategies to augment the functionality of T_PEX cells through niche modulation, stem-like CAR-T engineering, and combinatorial approaches, highlighting the trend that targeting T_PEX cells thus emerge as a transformative future strategy to overcome immunotherapy resistance and achieve a durable response.