Temperature as a Neglected Variable in Cancer: Cell-Intrinsic Thermal Sensitivity, Fever-Range Immunity, and the Febrile Paradox

Temperature is a fundamental physical variable affecting protein folding, proteostasis, cell-cycle kinetics, and immune function, yet cancer cell biology is performed almost exclusively at a fixed 37 °C, and distinct thermal phenomena are often conflated under the single term “hyperthermia.” This review examines the biology of mild, fever-range temperature excursions of approximately 38–41 °C, which are mechanistically distinct from externally induced hyperthermia. We synthesize three strands of evidence that have rarely been considered together. First, tumor cells display heterogeneous thermal sensitivity, with differences in growth, cell-cycle responses, and thermal tolerance that may reflect intrinsic molecular features and proteostatic reserve, including the heat-shock response mediated by HSF1 and HSP70/HSP90. Second, fever-range temperatures remodel antitumor immunity across innate and adaptive compartments, affecting immune-cell trafficking, membrane organization, metabolism, and tumor–immune recognition. Third, the clinical record appears controversial: febrile infections have been associated with lower subsequent cancer risk, whereas postoperative fever has been associated with worse prognosis. We argue that these observations cannot be interpreted without considering host state, timing, and the biological context in which temperature elevation occurs. The three evidence streams are of unequal strength: cell-intrinsic thermal sensitivity and fever-range immune effects rest on direct experimental data, much of it from colorectal cancer, which we adopt as the principal proof-of-concept model, whereas the clinical associations are largely retrospective, and we treat them with correspondingly different confidence. We therefore frame a central testable question: is cell-intrinsic thermal sensitivity a cause or a correlate of fever’s effects on cancer? We propose an experimental agenda that separates cell-autonomous thermal responses from host-mediated effects and establishes temperature as an explicit, biologically informative variable in cancer research.