{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:28:24Z","timestamp":1792787304265,"version":"4.5.0"},"reference-count":34,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"unspecified","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Five Five Engineering Projects of the Third Affiliated Hospital of Sun Yat-sen University","award":["2023WW502"],"award-info":[{"award-number":["2023WW502"]}]},{"name":"Key Science & Technology Project of Guangzhou City","award":["SL2023A03J00413"],"award-info":[{"award-number":["SL2023A03J00413"]}]},{"name":"Special Foundation Project of Guangdong Province","award":["0620220203"],"award-info":[{"award-number":["0620220203"]}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2024A151501148"],"award-info":[{"award-number":["2024A151501148"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,9,22]]},"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Patients with colon cancer liver metastases (CCLM) frequently exhibit poor responses to immunotherapy, a phenomenon attributed in part to an immune desert tumor microenvironment. This study aimed to comprehensively characterize the immune landscape in primary colon cancers and their matched liver metastases via single-cell transcriptome analysis, with the goal of identifying potential immunotherapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Tumor specimens from patients with CCLM were subjected to single-cell RNA sequencing. Immune subpopulations were profiled with emphasis on exhausted T cells (Tex)\u2014including both CD8\n                      <jats:sup>+<\/jats:sup>\n                      and CD4\n                      <jats:sup>+<\/jats:sup>\n                      ANK3\n                      <jats:sup>+<\/jats:sup>\n                      subsets\u2014as well as on a distinct stress response T-cell subset (TSTR) defined by high HSPA1A\/HSPA1B expression. In parallel, we performed assessments of the phenotype and prognostic impact of SPP1\n                      <jats:sup>high<\/jats:sup>\n                      myeloid cells, along with\n                      <jats:italic>in vitro<\/jats:italic>\n                      assays to examine their role in modulating T-cell number and function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Liver metastatic lesions exhibited a significantly elevated infiltration of Tex compared with primary tumors. Notably, Tex cells exhibited upregulated expression of exhaustion-related marker genes such as ANK3, ZBTB20, ETV6, and CAMK4, which were markedly downregulated in TSTR cells. TSTR was identified as an intermediate developmental state between effector and exhausted T cells in patients with CCLM, suggesting that TSTR cells represent a distinct state from exhausted T cells. Furthermore, myeloid cells expressing high levels of secreted phosphoprotein 1 (SPP1), along with apolipoprotein C-I and apolipoprotein E, were associated with poor prognosis in patients with CCLM.\n                      <jats:italic>In vitro<\/jats:italic>\n                      studies revealed that Macro_SPP1\n                      <jats:sup>high<\/jats:sup>\n                      cells diminished T-cell populations and triggered a stress response state in both CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells via the SPP1\/CD44\/PI3K\/AKT signaling pathway in a CD44-dependent manner. Importantly, combination treatment with anti-SPP1 and anti-programmed cell death protein-1 antibodies significantly inhibited liver metastasis growth, enhanced dendritic cell maturation, decreased M2-polarized macrophages, and restored T-cell infiltration and function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings reveal a previously unrecognized relationship between Macro_SPP1\n                      <jats:sup>high<\/jats:sup>\n                      cells and HSPA1A\n                      <jats:sup>high<\/jats:sup>\n                      \/HSPA1B\n                      <jats:sup>high<\/jats:sup>\n                      T cells in driving CCLM progression, suggesting a potential synergistic therapeutic approach that could boost immune checkpoint treatment efficacy in patients with CCLM.\n                    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