MedComm · Published 2026-08-01 · DOI 10.1002/mco2.70882
Xiao Ge, Dong Han, Jing Wang, Xinyu Dai, Chen Ma, Feihong Chen
ABSTRACT The prevailing view of cold tumors as a singular immune‐insensitive state is not merely imprecise, which is clinically misleading. Currently, we contend that cold tumors comprise a heterogeneous spectrum of resistance ecosystems by distinct, coexisting, dominant barriers. We argue that a universal “heating” strategy is unlikely to succeed; instead, durable clinical benefit will depend on barrier‐directed immune reprogramming. We dissect this heterogeneity by linking a set of core mechanistic drivers to canonical hot, immune‑desert, and immune‐excluded phenotypes. The drivers include defective antigen processing and presentation, impaired T‐cell priming, physical exclusion by aberrant vasculature, stromal components, metabolic exhaustion, and adaptive resistance. Our evaluation of emerging conversion strategies focuses not on their novelty but on capacity to neutralize a specific rate‐limiting barrier. We also examine why combination and sequencing are indispensable, highlight translational gaps between preclinical models and human disease and propose a dynamic biomarker framework that extends beyond static PD‐L1 assessment to capture real‐time shifts in dominant barrier. Our central conclusion is that durable cold‐to‐hot conversion will require iterative, biomarker‐guided and barrier‐adaptive interventions that evolve alongside tumor counter‐adaptation. The reframing positions immunotherapy resistance not as a terminal obstacle but as a manageable, dynamic challenge, offering a practical strategy for clinical translation.
Abstract from DOAJ. Public domain (CC0 1.0).
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Ge, X., Han, D., Wang, J., et al. (2026). Turning Cold Tumors Into Hot Tumors: Implications for Cancer Therapy. MedComm. https://doi.org/10.1002/mco2.70882