Immunometabolic Gatekeeping: Reconciling Peto's & the T-cell Infiltration Prognostic Paradox.

Classical models of cancer focus on tumour-intrinsic genetic aberrations and immune dynamics and often overlook how the metabolic environment of healthy tissues shapes tumour development and immune efficacy. Here, we propose that tissue-intrinsic metabolic intensity and waste-handling capacity act as an upstream gatekeeper of anti-tumour immunity, determining whether immune infiltration translates into effective immune function and safeguards the tissue from tumourigenesis. Across human cancers, tumours arising in high-metabolism tissues - like kidney, brain, and eye - tend to show high T cell infiltration but poor prognosis, suggesting pre-existing metabolic environments prior to malignant transformation may undermine immune function. This pattern is mirrored across species: large mammals with lower mass-specific metabolic rates (e.g., elephants, whales) accumulate fewer metabolic byproducts and show lower cancer incidence (Peto's paradox), while long-lived small mammals like bats and naked mole-rats resist tumourigenesis via suppressed glycolysis or altered hypoxia responses leading to lower metabolic rates and/or byproduct accumulation. Through integrative synthesis spanning human single-cell expression data and cross-species comparisons, we outline a framework of "immunometabolic gatekeeping," where tissues with high metabolic rate and poor waste clearance foster immune-exhausting niches even before transformation. This unifying framework reconciles multiple paradoxes in cancer biology: Peto's paradox, T cell infiltration non-prognosticity, tissue tropisms, sex-based inequalities, and size-based tipping points (e.g., the 3 cm rule in ccRCC), and suggests new principles for identifying high-risk patients and metabolic-immune combination strategies for prevention and treatment. By shifting focus from tumour-intrinsic mutations to host-tissue metabolism, this work offers a novel, integrative lens on cancer vulnerability and immune failure.