# Cuproptosis at the Crossroads of Tumor Microenvironment Inflammation and Metabolic Rewiring Mechanisms and Therapeutic Opportunities

## TL;DR

This review explores how copper-induced cell death (cuproptosis) interacts with tumor inflammation and metabolism, offering new therapeutic strategies for cancer treatment.

## Contribution

The paper introduces cuproptosis as a novel regulated cell death mechanism with unique immunogenic potential in the tumor microenvironment.

## Key findings

- Cuproptosis is linked to copper dysregulation and can trigger immunogenic reactions via DAMPs like CRT and HMGB1.
- Copper addiction in tumors creates a vulnerability exploitable through cuproptosis-inducing therapies.
- Cuproptosis-based strategies may reprogram cold tumors and synergize with immunotherapies.

## Abstract

Metabolic reorganization and chronic inflammation are dynamic and diverse events in the tumor microenvironment (TME) that cause tumor propagation, spreading, and resistance to treatment. However, copper‐induced cell death (cuproptosis), which is a newly discovered form of regulated cell death (RCD) induced by high intracellular copper ions and is a common location coupled with the tricarboxylic acid cycle (TCA), has promptly become a hub of metal homeostasis, cellular metabolism, and immune regulation within the TME. This review will consider cuproptotic molecular pathways. We focus on how inflammatory cytokines and hypoxia directly influence copper uptake, intracellular traffic, and the cell death threshold. Compared with other more predominant types of RCD, we highlight the capacity of cuproptosis to trigger numerous potent immunogenic reactions by releasing damage‐associated molecular patterns (DAMPs), including calreticulin (CRT), ATP, HMGB1, and type I interferons (IFNs). The reciprocal crosstalk between copper dysregulation and chronic inflammation fuels tumor angiogenesis and invasion by fostering “copper addiction.” However, this metabolic dependency simultaneously creates a distinct vulnerability. We examine how inducing cuproptosis—conceptually distinct from simple copper accumulation—exploits this fragility to release DAMPs and reprogram the immune microenvironment of “cold” tumors. Such therapeutic strategies, spanning copper ionophores, chelators, and novel nanomedicines, offer significant potential to synergize with immunotherapies and overcome treatment resistance. Despite encouraging preclinical research results, some obstacles still need to be overcome, such as the cuproptosis‐specific modulation’s functionality, systemic toxicity reduction, and tumor heterogeneity. In order to transfer the curing power of cuproptosis directly into the medical practice, several key issues must be addressed in the future. These involve optimizing in vivo models to enhance physiological relevance, measuring cell‐type‐specific sensitivity, identifying reliable biomarkers, and utilizing highly sensitive modulators. The benefits of cuproptosis therapy will inevitably lead to the development of a novel healing strategy, which involves reorganizing the inflamed and immunosuppressive TME through cuproptosis, resulting in sustained and effective antitumor effects.