Figure 1. Model of intratumoral CD8⁺ T cell states.

This schematic depicts a model describing the characteristics of, and possible connections between, the major CD8⁺ T cell states in human tumors, as based on data from^{20–22,28–31,33,34}. Observations from the different studies that support this model are listed in Supplementary Table S1. In brief, the naïve-like cells described in non-small-cell lung cancer (NSCLC)²⁹, hepatocellular carcinoma (HCC)²⁸, colorectal cancer (CRC)³¹, basal cell cancer (BCC)³⁰, and melanoma²¹ show a strong resemblance to the (central-)memory populations described by Sade-Feldman et al. and Clarke et al.^22,33. Based on the expression of granzyme K (GZMK), intermediate expression of inhibitory molecules, and relatively low clonality, the T lymphocyte population described in Sade-Feldman et al.²² and the effector–memory population described in Zhang et al.³¹ were considered similar to the pre-dysfunctional cell states observed in melanoma²¹, HCC28, and NSCLC²⁹. While additional research is required to determine their extent of overlap, the tissue resident memory T (T_RM) population described in triple-negative breast cancer (TNBC)³⁴ and the HAVCR2+ T_RM cells in NSCLC³³ are here aligned with the dysfunctional state described in all other studies. The cell state definitions from Azizi et al.³² could not be integrated into the model presented here and the effector–memory subset reported by Savas et al. may be composed of a mixture of pre-dysfunctional and cytotoxic cells, based on the combined expression of GZMK and killer cell lectin-like receptor subfamily G member 1 (KLRG1)³⁴. In this model, we propose that the development of (pre-)dysfunctional cell states is predominantly driven by tumor-specific cues such as tumor antigen recognition and/or tumor-specific environmental factors (here referred to as tumor microenvironment (TME)-induced differentiation). Cytotoxic cell states are also encountered in healthy tissues^28,29,31, indicating that the underlying differentiation process is not strictly tumor-specific (here referred to as TME-independent differentiation). Cytotoxic effector T cells are depicted as a population that is most likely developmentally distinct from the cells along the (pre-)dysfunctional axis, but additional research is required to clarify whether cytotoxic effector cells indeed originate from a distinct pool of cells, or whether they are connected to the (pre-)dysfunctional axis in some situations (as depicted by the dashed two-way arrow). Note that both trajectory and T cell receptor (TCR) sharing analyses indicate that the pre-dysfunctional and dysfunctional cells form a continuum of cell states, rather than well-demarcated populations. The line graph shows approximate levels of proliferation, CXC-chemokine ligand 13 (CXCL13) expression, and the expression of inhibitory receptors by pre-dysfunctional, early dysfunctional, and late dysfunctional CD8⁺ T cells. CCR7, CC-chemokine receptor 7; CX3CR1, CX3C chemokine receptor 1; CTLA4, cytotoxic lymphocyte-associated antigen 4; FCGR3A, Fcγ receptor IIIA; IL7R, interleukin 7 receptor; LAG3, lymphocyte activation gene 3; PDCD1, programmed cell death 1; PRF1, perforin 1; TCF7, transcription factor 7.