A lactate-mitochondrial axis framework for mild hyperthermia and checkpoint blockade in driver-negative NSCLC: testing temporal coupling

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.