{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T05:49:23Z","timestamp":1782107363197,"version":"3.54.5"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Under chronic infections or in tumors, persistent antigen exposure drives CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell exhaustion, a heterogeneous state encompassing a differentiation continuum from stem-like progenitor (Tpex) cells through transitory effector-like (Tex-int) cells to terminally exhausted (Tex-term) subsets. Among these T cell subsets, Tex-int cells serve as the primary population responsible for direct tumor cell killing. However, the intrinsic regulatory mechanisms that govern the Tpex-to-Tex-int transition remain incompletely defined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this study, we explore the role of special AT-rich sequence-binding protein 1 (SATB1) in the differentiation of Tex-int cells from their precursors. We observed downregulation of SATB1 during Tpex-to-Tex-int differentiation in tumors. Notably, the genetic ablation of\n                      <jats:italic>Satb1<\/jats:italic>\n                      in T cells markedly expanded the population of tumor-infiltrating CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells (CD8\n                      <jats:sup>+<\/jats:sup>\n                      TILs).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Ablating\n                      <jats:italic>Satb1<\/jats:italic>\n                      not only promoted the differentiation of Tex-int cells from Tpex cells within the tumor microenvironment but also remodeled T cell differentiation in tumor-draining lymph nodes (TdLNs) by expanding the Tpex pool from tumor-specific memory CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells (T\n                      <jats:sub>TSM<\/jats:sub>\n                      ) and driving the Tpex1 to Tpex2 transition, thereby augmenting Tex-int production in tumors. Although early-stage Tex-int cells in\n                      <jats:italic>Satb1<\/jats:italic>\n                      -deficient mice displayed transient functional impairment relative to controls, this difference was no longer evident in late-stage tumors, where sustained Tex-int accumulation correlated with significantly suppressed tumor growth and prolonged survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Our results identify SATB1 as a pivotal regulator of exhausted CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell subset differentiation and suggest its targeting as a promising strategy to expand the Tex-int population for enhanced cancer immunotherapy.\n                    <\/jats:p>\n                  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