Mitochondria-Associated Endoplasmic Reticulum Membranes in Cancer: Hubs for Tumor Progression and Therapeutic Vulnerabilities.

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic contact sites between the endoplasmic reticulum (ER) and mitochondria that coordinate multiple cellular processes such as calcium signaling, lipid trafficking, and redox homeostasis. Increasing evidence shows that cancer cells remodel MAMs to support metabolic adaptation, stress tolerance, tumor progression, and therapeutic resistance. In this review, we summarize the structural organization of MAMs, the core tethering and regulatory mechanisms governing their plasticity, and emerging evidence linking MAM dysfunction to malignant phenotypes and therapeutic resistance. We highlight that the roles of MAM-associated proteins in cancer are highly context-dependent, varying with tumor type, metabolic state, and therapeutic pressure. We further discuss emerging therapeutic strategies targeting MAM-associated pathways, as well as combination approaches to overcome resistance. A better mechanistic understanding of MAM remodeling may reveal actionable vulnerabilities and support biomarker-guided precision therapy across cancer types.