# Obesity and Cancer: From Systemic Metabolic Reprogramming to Immunotherapy Paradox

## TL;DR

Obesity promotes cancer by altering metabolism and the tumor environment, and combining metabolic treatments with immunotherapy could improve cancer outcomes.

## Contribution

A multi-layered framework linking systemic obesity signals to tumor microenvironment barriers and proposing new treatment strategies.

## Key findings

- Obesity drives tumorigenesis through metabolic, hormonal, and inflammatory changes that condition the tumor microenvironment.
- Conventional metrics like BMI are insufficient to capture cancer-relevant obesity exposures.
- Combining metabolic interventions with immunotherapy may reverse immune exhaustion and improve treatment outcomes.

## Abstract

What are the main findings?
Obesity drives tumorigenesis through coordinated metabolic, hormonal, and inflammatory remodeling that precedes and conditions tumor microenvironment (TME) barriers.The review proposes a multi-layered framework connecting systemic obesity-driven signals (e.g., insulin–IGF axis, leptin–PD-1 signaling, aromatase expression, histone lactylation) with local TME execution modules (perfusion, ECM, immune exhaustion).

Obesity drives tumorigenesis through coordinated metabolic, hormonal, and inflammatory remodeling that precedes and conditions tumor microenvironment (TME) barriers.

The review proposes a multi-layered framework connecting systemic obesity-driven signals (e.g., insulin–IGF axis, leptin–PD-1 signaling, aromatase expression, histone lactylation) with local TME execution modules (perfusion, ECM, immune exhaustion).

What are the implications of the main findings?
Conventional metrics like BMI are insufficient to capture cancer-relevant obesity exposures. Markers such as leptin/adiponectin ratio, histone lactylation, or checkpointIntegrating metabolic intervention (e.g., GLP-1-based agents) with immunotherapy may unlock new combination strategies by reversing pseudo-exhaustion and modifying checkpoint sensitivity.

Conventional metrics like BMI are insufficient to capture cancer-relevant obesity exposures. Markers such as leptin/adiponectin ratio, histone lactylation, or checkpoint

Integrating metabolic intervention (e.g., GLP-1-based agents) with immunotherapy may unlock new combination strategies by reversing pseudo-exhaustion and modifying checkpoint sensitivity.

With the global rise in overweight and obesity, excess adiposity has emerged as a modifiable carcinogenic exposure. Beyond energy surplus, obesity establishes a durable pro-tumorigenic baseline through endocrine–metabolic rewiring, chronic low-grade inflammation, and structural/mechanical remodeling of tissues, thereby shaping organ-specific microenvironments that favor malignant transformation and progression. This review integrates systemic metabolic and endocrine alterations with tumor microenvironmental physical barriers, immune reprogramming, and neuroimmune regulation to explain heterogeneity in cancer risk, progression, and treatment response. We propose a stratified assessment framework based on measurable indicators—body composition, inflammatory status, and treatment exposure—to support risk prediction, mechanistic validation, and the design of actionable experimental and clinical strategies.