Immunometabolic Gatekeeping: Reconciling Peto's & the T-cell Infiltration Prognostic Paradox
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| Format: | Preprint |
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2025
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| author | Berg, Naomi Iris van den Elphick, Matouš Mulder, Kevin Bouricha, Omar Sadeghi-Alavijeh, Omid Fu, Xiao Turajlic, Samra |
| author_facet | Berg, Naomi Iris van den Elphick, Matouš Mulder, Kevin Bouricha, Omar Sadeghi-Alavijeh, Omid Fu, Xiao Turajlic, Samra |
| contents | 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. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2511_20883 |
| institution | arXiv |
| publishDate | 2025 |
| record_format | arxiv |
| spellingShingle | Immunometabolic Gatekeeping: Reconciling Peto's & the T-cell Infiltration Prognostic Paradox Berg, Naomi Iris van den Elphick, Matouš Mulder, Kevin Bouricha, Omar Sadeghi-Alavijeh, Omid Fu, Xiao Turajlic, Samra Tissues and Organs 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. |
| title | Immunometabolic Gatekeeping: Reconciling Peto's & the T-cell Infiltration Prognostic Paradox |
| topic | Tissues and Organs |
| url | https://arxiv.org/abs/2511.20883 |