Cell surface exposure of the inner membrane lipid phosphatidylserine (PS) is classically associated with cell death. Live T cells, however, have been shown to externalize PS, and the role of cell surface-exposed PS in T-cell function remains unclear. In this study, Medina and colleagues used the lymphocytic choriomeningitis virus (LCMV) mouse model of chronic infection to decipher the effects of PS exposure by T cells during sustained antigen stimulation, a process highly relevant to cancer. In both acute and chronic LCMV-infected mice, PS was detected on the surface of antigen-specific, but not naïve, CD8+ T cells, indicating that T-cell activation induces PS exposure. Surface PS levels decreased as the infection resolved in acute LCMV-infected mice but increased as CD8+ T cells transitioned from stem-like to transitory to terminally differentiated/exhausted in chronically infected mice. Treatment with a PS-targeting antibody increased the number of stem-like, transitory, and effector antigen-specific CD8+ T cells in chronic LCMV-infected mice, resulting in an enhanced antiviral response. PS blockade was found to enhance both proliferation and differentiation signatures in stem-like CD8+ T cells, demonstrating that PS exposure inhibits their expansion and maturation. In adoptive transfer experiments, PS-targeting antibody induced the expansion of donor stem-like, but not effector, CD8+ T cells in recipient mice. Moreover, PS blockade augmented the ability of conventional type I dendritic cells (cDC1) to present antigen and activate stem-like CD8+ T cells via upregulation of the costimulatory molecule CD86. Treatment with both a PS-targeting antibody and anti-PD-L1 produced stronger antigen-specific CD8+ T-cell responses than either treatment alone. Finally, intratumoral CD8+ T cells were also confirmed to externalize PS in levels that corresponded with their differentiation state in patients with clear cell renal cell carcinoma or non-small-cell lung cancer. Altogether, results from this study propose PS as an extrinsic inhibitory T-cell molecule and support the therapeutic potential of PS blockade in combination with checkpoint inhibition in treating cancer and chronic infections.Medina CB, Sobierajska E, Gong M, McManus DT, Thapa M, Lee J, et al. Exposed phosphatidylserine is an inhibitory molecule in T cell exhaustion. Nature 2026 Mar 25 Epub ahead of print.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.
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