# Immunometabolic crosstalk between tumor- associated macrophages and ferroptotic cancer cells: mechanisms, regulation, and therapeutic applications

## TL;DR

This paper explores how tumor-associated macrophages influence cancer cell death through a process called ferroptosis, and how this interaction could be used to improve cancer treatments.

## Contribution

The paper provides a comprehensive review of the immunometabolic crosstalk between TAMs and ferroptotic cancer cells, highlighting novel therapeutic strategies.

## Key findings

- TAMs modulate ferroptosis through metabolic cues like iron flux and redox balance.
- TAM-derived cytokines and lipid mediators influence ferroptotic cell death in tumors.
- Rewiring TAM metabolism could enhance cancer immunotherapy effectiveness.

## Abstract

Tumor-associated macrophages (TAMs) are central regulators of the metabolic and immunological landscape of solid tumors and are increasingly recognized as key determinants of cancer-cell susceptibility to ferroptosis. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, is tightly shaped by metabolic cues within the tumor microenvironment (TME). TAMs, through their remarkable metabolic plasticity, modulate iron flux, redox balance, polyunsaturated fatty-acid (PUFA) availability, and glutathione-dependent antioxidant pathways, each of which directly influences ferroptotic vulnerability in neighboring tumor cells. In this review, we synthesize current evidence linking TAM polarization states to the regulation of ferroptosis-related processes, including lipid remodeling, cystokine metabolism, reactive oxygen species (ROS) buffering, and immunometabolic signaling. We further discuss how TAM-derived cytokines, lipid mediators, and iron-handling proteins orchestrate a microenvironment that either promotes or restrains ferroptotic cell death. Finally, we highlight emerging therapeutic strategies aimed at rewiring TAM metabolism or exploiting ferroptosis to overcome immune suppression and therapy resistance. By integrating immunological and metabolic dimensions, this review provides a framework for understanding TAM-ferroptosis crosstalk and its implications for precision immunotherapy in cancer.