A lactate–mitochondrial axis framework for mild hyperthermia and checkpoint blockade in driver-negative NSCLC: testing temporal coupling
- 1North Sichuan Medical College
- 2Department of Oncology, Affiliated Hospital of North Sichuan Medical College
- 3Key Laboratory of Integrated Precision Diagnosis and Treatment for Solid Tumors, Sichuan Provincial Health Commission
Abstract
Metabolic constraints, including hypoxia, lactate, and adenosine that impair CD8 ⁺ T-cell function and mitochondrial fitness, are increasingly recognized as contributors to resistance to immune checkpoint inhibitors (ICIs) in driver-negative (lacking an established first-line actionable driver alteration) advanced non-small cell lung cancer (NSCLC). We propose a hypothesis-driven framework asking whether transient tissue-level metabolic relief can be temporally aligned with the slower process of T-cell reinvigoration driven by immune checkpoint blockade (ICB). Its mechanistic basis is a lactate–mitochondrial axis linking extracellular metabolic suppression to mitochondrial states in tumor-infiltrating T cells, with T-cell-intrinsic mitochondrial adaptation treated as a testable extension. Locoregional mild hyperthermia (39–42 °C) is conceptualized as a transient modulator of tissue-level metabolic gradients rather than a direct immune activator. Because oxygenation, metabolite distribution, and acid–base status may change independently or in opposing directions, oxygenation is treated as a physiological readout rather than a surrogate for metabolic relief. We define a relief window as transient attenuation of hypoxic constraint accompanied by redistribution of lactate and adenosine away from T-cell-containing regions. Because such windows are short relative to ICB-driven reinvigoration, their therapeutic relevance may depend on recurrent temporal overlap, quantified through coverage and placement using provisional criteria at graded levels of evidence. The framework is proposed to apply primarily to glycolytic, hypoxic tumors retaining reinvigoration-competent progenitor exhausted T cells, with KRAS/STK11 co-mutant and KEAP1-altered NSCLC prioritized for testing as indicators of metabolic phenotype rather than predictors of benefit, subject to baseline confirmation that a reinvigoration-competent T-cell compartment is present. We specify necessary conditions, enabling requirements, and failure conditions, together with safety monitoring for repeated heating, while treating local-to-systemic immune propagation as an optional extension. A phase 0 strategy is proposed to establish whether reproducible candidate relief windows can be detected in patients, before efficacy testing and before any inference of clinical benefit.
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BibTeX
@article{liu2026lactatemitochondrial,
title = {{A lactate–mitochondrial axis framework for mild hyperthermia and checkpoint blockade in driver-negative NSCLC: testing temporal coupling}},
author = {Meihan Liu and Yaoshu Song and Hongpan Zhang and Yan Gui and Daiyuan Ma},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1969238},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1969238/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A lactate–mitochondrial axis framework for mild hyperthermia and checkpoint blockade in driver-negative NSCLC: testing temporal coupling
AU - Meihan Liu
AU - Yaoshu Song
AU - Hongpan Zhang
AU - Yan Gui
AU - Daiyuan Ma
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1969238
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1969238/full
AB - Metabolic constraints, including hypoxia, lactate, and adenosine that impair CD8 ⁺ T-cell function and mitochondrial fitness, are increasingly recognized as contributors to resistance to immune checkpoint inhibitors (ICIs) in driver-negative (lacking an established first-line actionable driver alteration) advanced non-small cell lung cancer (NSCLC). We propose a hypothesis-driven framework asking whether transient tissue-level metabolic relief can be temporally aligned with the slower process of T-cell reinvigoration driven by immune checkpoint blockade (ICB). Its mechanistic basis is a lactate–mitochondrial axis linking extracellular metabolic suppression to mitochondrial states in tumor-infiltrating T cells, with T-cell-intrinsic mitochondrial adaptation treated as a testable extension. Locoregional mild hyperthermia (39–42 °C) is conceptualized as a transient modulator of tissue-level metabolic gradients rather than a direct immune activator. Because oxygenation, metabolite distribution, and acid–base status may change independently or in opposing directions, oxygenation is treated as a physiological readout rather than a surrogate for metabolic relief. We define a relief window as transient attenuation of hypoxic constraint accompanied by redistribution of lactate and adenosine away from T-cell-containing regions. Because such windows are short relative to ICB-driven reinvigoration, their therapeutic relevance may depend on recurrent temporal overlap, quantified through coverage and placement using provisional criteria at graded levels of evidence. The framework is proposed to apply primarily to glycolytic, hypoxic tumors retaining reinvigoration-competent progenitor exhausted T cells, with KRAS/STK11 co-mutant and KEAP1-altered NSCLC prioritized for testing as indicators of metabolic phenotype rather than predictors of benefit, subject to baseline confirmation that a reinvigoration-competent T-cell compartment is present. We specify necessary conditions, enabling requirements, and failure conditions, together with safety monitoring for repeated heating, while treating local-to-systemic immune propagation as an optional extension. A phase 0 strategy is proposed to establish whether reproducible candidate relief windows can be detected in patients, before efficacy testing and before any inference of clinical benefit.
SN - 1664-3224
ER -