This research article investigates the mechanism by which stem-like CD8+ T cells (TSL), which are critical precursors for sustained anti-tumor responses, maintain their progenitor state despite chronic antigen exposure. The authors demonstrate that, contrary to traditional views, the inhibitory PD-1 pathway plays a crucial role by providing a negative-feedback loop that finely tunes the T-cell receptor (TCR) signaling intensity. This attenuation allows TSL cells with the highest TCR affinity to continuously proliferate and self-renew within specialized antigen-presentation niches in the tumor-draining lymph nodes. Crucially, checkpoint blockade that disables PD-1 inhibition disrupts this delicate balance, causing the high-affinity TSL population to undergo rapid terminal differentiation or cell death. The findings therefore suggest that while PD-1 blockade yields a powerful short-term anti-tumor effect, it may reduce long-term immunological maintenance by sacrificing the most potent progenitor cells.

References:

• Hor J L, Schrom E C, Wong-Rolle A, et al. Inhibitory PD-1 axis maintains high-avidity stem-like CD8+ T cells[J]. Nature, 2025: 1-11.