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<p>We integrated bulk, single-cell, and spatial transcriptomics to test whether intratumoral heterogeneity (ITH) aggravates CD8<sup>+</sup> T-cell exhaustion (TEX) in lung adenocarcinoma. In bulk cohorts, ITH and TEX were tightly coupled, with ITH-High tumors preferentially exhibiting deeper TEX phenotypes. This dually adverse (high ITH/high TEX) context was associated with increased antigenicity (higher TMB, predicted neoantigen and cancer/testis antigen scores) but reduced TCR diversity, lower global immune/stromal infiltration, more aggressive clinicogenomic features, and poorer survival. Joint ITH-TEX stratification further revealed an additive prognostic effect, with dual-low (low ITH/low TEX) best and dual-high (high ITH/high TEX) worst outcomes. Single-cell analyses implicated macrophages: ITH-High tumors exhibited coordinated upregulation of classical MHC-I antigen-presentation programs (processing/loading; <i>HLA-A/B/C</i> signaling), stronger macrophage→TEX communication, and enrichment of terminal TEX states. Spatially, in ITH-High tumors, TEX co-localized more closely with MHC-I<sup>high</sup> macrophage niches than with macrophages overall, whereas in ITH-Low tumors this proximity was attenuated. B cells showed increased TEX communication but inconsistent MHC-I state spatial coupling, while dendritic cells showed high proximity without ITH-dependent communication increases and weakened colocalization when restricted to MHC-I<sup>high</sup>. We also derived a six-gene decision-tree classifier (<i>CDC45</i>, <i>CENPF</i>, <i>PCLAF</i>, <i>SCGB3A1</i>, <i>CDCA8</i>, and <i>NDC80</i>) predicting ITH/TEX phenotypes. These data support a macrophage MHC-I axis linking ITH to terminal TEX and motivate combining checkpoint blockade with macrophage reprogramming or modulation of antigen-processing and presentation.</p>

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A macrophage MHC-I axis links intratumoral heterogeneity to terminal CD8+ T cell exhaustion in lung adenocarcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月25日

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  • Shangzhen Yin,
  • Haiyan Gao,
  • Qiang Li,
  • Mengrui Wang,
  • Peng Zhang,
  • Yurou Guo,
  • Pengyu Nan,
  • Weihao Kong,
  • Hongmei Shen,
  • Liqiang Wang,
  • Jianping Lu

摘要

We integrated bulk, single-cell, and spatial transcriptomics to test whether intratumoral heterogeneity (ITH) aggravates CD8+ T-cell exhaustion (TEX) in lung adenocarcinoma. In bulk cohorts, ITH and TEX were tightly coupled, with ITH-High tumors preferentially exhibiting deeper TEX phenotypes. This dually adverse (high ITH/high TEX) context was associated with increased antigenicity (higher TMB, predicted neoantigen and cancer/testis antigen scores) but reduced TCR diversity, lower global immune/stromal infiltration, more aggressive clinicogenomic features, and poorer survival. Joint ITH-TEX stratification further revealed an additive prognostic effect, with dual-low (low ITH/low TEX) best and dual-high (high ITH/high TEX) worst outcomes. Single-cell analyses implicated macrophages: ITH-High tumors exhibited coordinated upregulation of classical MHC-I antigen-presentation programs (processing/loading; HLA-A/B/C signaling), stronger macrophage→TEX communication, and enrichment of terminal TEX states. Spatially, in ITH-High tumors, TEX co-localized more closely with MHC-Ihigh macrophage niches than with macrophages overall, whereas in ITH-Low tumors this proximity was attenuated. B cells showed increased TEX communication but inconsistent MHC-I state spatial coupling, while dendritic cells showed high proximity without ITH-dependent communication increases and weakened colocalization when restricted to MHC-Ihigh. We also derived a six-gene decision-tree classifier (CDC45, CENPF, PCLAF, SCGB3A1, CDCA8, and NDC80) predicting ITH/TEX phenotypes. These data support a macrophage MHC-I axis linking ITH to terminal TEX and motivate combining checkpoint blockade with macrophage reprogramming or modulation of antigen-processing and presentation.