Metabolic‐Immune Crosstalk in Colorectal Cancer: Mechanisms and Therapeutic Opportunities

ABSTRACT Colorectal cancer (CRC) remains a major cause of cancer‐related morbidity and mortality worldwide, with its progression and therapeutic resistance increasingly recognized as consequences of complex metabolic and immune interactions within the tumour microenvironment (TME). Recent advances in single‐cell and spatial multi‐omics technologies have enabled detailed characterisation of metabolic heterogeneity among TME components, uncovering how distinct metabolic states influence immune function and therapeutic responses. In this review, we summarize recent advances in our understanding of metabolic regulation in the CRC microenvironment, with a particular focus on how distinct immune cell populations contribute to tumour progression and immune suppression through diverse metabolic pathways. We discuss key metabolite‐driven signalling networks involving lactate, short‐chain fatty acids, bile acids, and amino acid derivatives, and examine how these pathways influence immune cell function and tumour‐immune interactions. Furthermore, we highlight emerging therapeutic approaches targeting the metabolic‐immune axis, including glutaminase inhibitors, CD36 antagonists, and combination regimens integrating metabolic intervention with immune checkpoint inhibitors. By integrating recent mechanistic discoveries with therapeutic perspectives, this review provides an updated overview of the metabolic‐immune landscape in CRC and discusses potential strategies to exploit metabolic vulnerabilities for improving immunotherapy efficacy and overcoming treatment resistance.