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

TL;DR

Stem-like CD8+ T cells, called TPEX, are crucial for long-term cancer immunotherapy success and can be targeted to improve treatment outcomes.

Contribution

This review highlights the biology and therapeutic potential of TPEX cells in enhancing immunotherapy efficacy.

Findings

Stem-like CD8+ T cells correlate with better clinical outcomes in immunotherapy.

TPEX cells can self-renew and differentiate into effector and exhausted T cells.

Strategies to enhance TPEX functionality are being explored to overcome treatment resistance.

Abstract

The identification of stem-like CD8+ T cells, also termed progenitor or precursor of exhausted T cells (TPEX), 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 TPEX cells biology, highlighting interconnected research pillars, including: specialized niche microenvironments that sustain stemness of TPEX 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 TPEX cells as the primary driver of immunotherapy efficacy. Further, we explore strategies to augment the functionality of TPEX cells through niche modulation, stem-like CAR-T engineering, and combinatorial approaches, highlighting the trend that targeting TPEX cells thus emerge as a transformative future strategy to overcome immunotherapy resistance and achieve a durable response.

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