Circular RNAs Act as Molecular Bridges for Dual Regulation of Ferroptosis and Anti-tumor Immunity in Cancer

Ferroptosis, an iron-dependent, lipid peroxidation-driven regulated cell death, and the tumor immune microenvironment (TIME) are critical targets in cancer biology. Current cancer therapies often face limitations due to tumor heterogeneity and resistance mechanisms. Emerging evidence suggests that circular RNAs (circRNAs), stable single-stranded RNA molecules, possess diverse regulatory functions beyond classical coding RNAs. Understanding how these distinct pathways (cell death and immunity) are interconnected, and how circRNAs might orchestrate this crosstalk, represents a significant gap in developing more effective and precise cancer therapies.

This review systematically elaborated on the molecular mechanisms by which circRNAs mediate crosstalk between ferroptosis and anti-tumor immunity in cancer. The authors defined a novel concept of 'dual regulation,' where circRNAs simultaneously target key nodes in both pathways via a single regulatory event. They focused on three major regulatory modalities: miRNA sponging, protein interaction/scaffolding, and de novo encoding of functional peptides. The review explored the potential of these circRNAs as non-invasive diagnostic biomarkers and novel therapeutic targets, providing new perspectives for precision cancer therapy.

The review established that circRNAs act as "molecular bridges" to simultaneously regulate ferroptosis and anti-tumor immunity in cancer. This "dual regulation" occurs through several key mechanisms. CircRNAs can function as miRNA sponges, sequestering specific miRNAs that would otherwise regulate genes involved in either ferroptosis or immune responses. They also act as protein scaffolds or interactors, modulating the activity or localization of proteins crucial for these pathways. Furthermore, some circRNAs are capable of de novo encoding functional peptides, which can directly influence cell death or immune cell function. The authors highlighted that ferroptosis and anti-tumor immunity reciprocally regulate each other through inflammatory signals and immune effectors, with circRNAs orchestrating this complex interplay. This systematic elaboration provides a comprehensive understanding of how these distinct biological processes are integrated at the molecular level.

The review defines 'dual regulation' as circRNAs simultaneously targeting key nodes in both ferroptosis and anti-tumor immunity pathways via a single regulatory event.