临床上有关鉴别不同高机能状况下肿瘤相关CD8+T细胞的免疫生物标志物仍存在争议。通过对多个患者队列和肿瘤类型中CD8+T细胞特征的多组学分析，我们发现了肿瘤微环境依赖性筋疲力尽和其他类型的CD8+T细胞低机能状况。在“有支持性”的微环境，如黑色素瘤或肺癌中，CD8+T细胞表现出肿瘤反应驱动的疲劳（CD8+ TEX）特征。这些特征包括熟练的效应器记忆表型，与效应器疲劳信号相关的扩展T细胞受体（TCR）库以及由大部分共有的癌症抗原或新抗原组成的癌症相关T细胞激活免疫肽组。相反，“无支持性”的微环境，如胶质母细胞瘤，富含不同于规范疲劳的低机能特征。这包括不成熟或未充分激活的T细胞状态，高愈合反应信号，与抗炎信号相关的非扩展TCR库，高T细胞可识别自表位点和与应激或促细胞凋亡反应相关的抗增殖状态。在胶质母细胞瘤的原位空间映射中，突显了功能失调的CD4+：CD8+T细胞相互作用的普遍存在，而体外单细胞分泌物映射对胶质母细胞瘤CD8+T细胞证实了微弱的效应器功能和类似促髓样，愈合性化学因子概况。在免疫肿瘤学临床试验中，抗程序性细胞死亡蛋白1（PD-1）免疫疗法促进了胶质母细胞瘤的耐受性差异，而树突状细胞（DC）疫苗部分纠正了它们。因此，接受胶质母细胞瘤DC疫苗的受体具有高效应器记忆CD8+T细胞和抗原特异性免疫的证据。综上所述，我们提供了一个用于评估免疫原性与非免疫原性癌症中不同CD8+T细胞低机能状况的图谱。

Clinically relevant immunological biomarkers that discriminate between diverse hypofunctional states of tumor-associated CD8+ T cells remain disputed. Using multiomics analysis of CD8+ T cell features across multiple patient cohorts and tumor types, we identified tumor niche-dependent exhausted and other types of hypofunctional CD8+ T cell states. CD8+ T cells in "supportive" niches, like melanoma or lung cancer, exhibited features of tumor reactivity-driven exhaustion (CD8+ TEX). These included a proficient effector memory phenotype, an expanded T cell receptor (TCR) repertoire linked to effector exhaustion signaling, and a cancer-relevant T cell-activating immunopeptidome composed of largely shared cancer antigens or neoantigens. In contrast, "nonsupportive" niches, like glioblastoma, were enriched for features of hypofunctionality distinct from canonical exhaustion. This included immature or insufficiently activated T cell states, high wound healing signatures, nonexpanded TCR repertoires linked to anti-inflammatory signaling, high T cell-recognizable self-epitopes, and an antiproliferative state linked to stress or prodeath responses. In situ spatial mapping of glioblastoma highlighted the prevalence of dysfunctional CD4+:CD8+ T cell interactions, whereas ex vivo single-cell secretome mapping of glioblastoma CD8+ T cells confirmed negligible effector functionality and a promyeloid, wound healing-like chemokine profile. Within immuno-oncology clinical trials, anti-programmed cell death protein 1 (PD-1) immunotherapy facilitated glioblastoma's tolerogenic disparities, whereas dendritic cell (DC) vaccines partly corrected them. Accordingly, recipients of a DC vaccine for glioblastoma had high effector memory CD8+ T cells and evidence of antigen-specific immunity. Collectively, we provide an atlas for assessing different CD8+ T cell hypofunctional states in immunogenic versus nonimmunogenic cancers.