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

TL;DR

This paper introduces a new framework called 'immunometabolic gatekeeping' that explains how tissue metabolism influences immune effectiveness and cancer development, reconciling several paradoxes in cancer biology.

Contribution

It proposes that tissue-intrinsic metabolic traits determine immune infiltration efficacy and cancer risk, integrating cross-species data and resolving longstanding paradoxes.

Findings

High-metabolism tissues show high T cell infiltration but poor prognosis.

Lower metabolic rates in large mammals correlate with lower cancer incidence.

Tissue metabolic environment influences immune exhaustion and tumorigenesis.

Abstract

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, and sex-based inequalities, 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.