Edited by: Tonya J Webb, University of Maryland, United States
Reviewed by: Mesut Yigit, My Gene and Cell Therapies Biotechnology, Türkiye
*Correspondence: Peishan Yu,
†These authors have contributed equally to this work
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The study by Lee et al. addresses a timely question: how T-cell exhaustion heterogeneity influences CRC outcomes, a heterogeneity now recognized to involve distinct functional subsets defined by co-inhibitory receptor combinations (
The TMA design—two 1-mm cores each from tumor center (TC) and invasive margin (IM)—risks underrepresenting spatial heterogeneity. Tertiary lymphoid structures (TLS), critical niches for Tpex, were excluded, potentially skewing exhaustion subset distributions. This approach directly contradicts spatial analyses demonstrating TLS as critical reservoirs for Tpex (
Ttex was defined solely as TCF1-PD1+CD8+, overlooking co-inhibitory receptors (e.g., TIM-3, LAG-3) that define terminal exhaustion. Recent single-cell studies (
The link between Ttex and oxaliplatin response remains correlative. Oxaliplatin induces immunogenic cell death (ICD), potentially activating Ttex. However,
Lee et al. provide foundational evidence that Ttex may refine CRC prognostication, but translating this into clinical utility requires three synergistic advances: spatially resolved whole-slide mIF must replace TMAs to incorporate tertiary lymphoid structures and ensure reliable invasive margin analysis, multi-parametric exhaustion signatures integrating ≥3 markers (e.g., PD-1+TCF1−TIM-3+) should be deployed via hyperplexed platforms like CODEX to distinguish functional subsets, and Ttex responsiveness must be functionally interrogated in immunogenic cell death models with/without anti-PD-1 to identify therapeutic synergies—particularly as the prognostic value of Ttex in CD8-low tumors holds revolutionary potential for adjuvant stratification, making validation in biomarker-driven trials such as FOxTROT with serial pre/post-chemotherapy mapping a critical next step.
WW: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. YL: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. PY: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – review & editing. LY: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – review & editing.
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