The endoplasmic reticulum (ER)-mitochondria axis, particularly through mitochondria-associated ER membranes (MAMs), plays a crucial role in cancer diagnosis and therapy. MAMs are essential for calcium homeostasis, lipid metabolism, and mitochondrial dynamics, and their dysfunction is linked to various diseases, including cancer. MAM proteins regulate intracellular signaling pathways, enhance cancer cell sensitivity to anticancer drugs, and modulate immune cell activities. Recent research highlights the importance of MAM proteins in cancer progression and their potential as diagnostic and therapeutic targets. Key MAM proteins involved in calcium regulation include IP3R, GRP75, VDAC, and MCU, while those involved in lipid metabolism include PSS1/2, PSD, PEMT, and Mdm12-Mmm1-Mdm34-Mdm10. MAM proteins also regulate mitochondrial dynamics through DRP1 and MFN1/2, and are involved in mitophagy via the PINK1/Parkin pathway. Additionally, MAM proteins such as ERO1, Sig-1R, p66Shc, and MFN2 are implicated in oxidative stress and ER stress, which are critical in cancer development. Targeting MAM proteins offers therapeutic potential by modulating calcium signaling, lipid metabolism, and ER stress. Drugs like cisplatin, adriamycin, and mipsagargin target MAM proteins to induce apoptosis and reduce resistance in cancer cells. Furthermore, MAM proteins such as PDZD8 and VAPB are potential diagnostic markers for cancer. Overall, understanding the role of MAM proteins in cancer provides insights into their potential as diagnostic and therapeutic targets.The endoplasmic reticulum (ER)-mitochondria axis, particularly through mitochondria-associated ER membranes (MAMs), plays a crucial role in cancer diagnosis and therapy. MAMs are essential for calcium homeostasis, lipid metabolism, and mitochondrial dynamics, and their dysfunction is linked to various diseases, including cancer. MAM proteins regulate intracellular signaling pathways, enhance cancer cell sensitivity to anticancer drugs, and modulate immune cell activities. Recent research highlights the importance of MAM proteins in cancer progression and their potential as diagnostic and therapeutic targets. Key MAM proteins involved in calcium regulation include IP3R, GRP75, VDAC, and MCU, while those involved in lipid metabolism include PSS1/2, PSD, PEMT, and Mdm12-Mmm1-Mdm34-Mdm10. MAM proteins also regulate mitochondrial dynamics through DRP1 and MFN1/2, and are involved in mitophagy via the PINK1/Parkin pathway. Additionally, MAM proteins such as ERO1, Sig-1R, p66Shc, and MFN2 are implicated in oxidative stress and ER stress, which are critical in cancer development. Targeting MAM proteins offers therapeutic potential by modulating calcium signaling, lipid metabolism, and ER stress. Drugs like cisplatin, adriamycin, and mipsagargin target MAM proteins to induce apoptosis and reduce resistance in cancer cells. Furthermore, MAM proteins such as PDZD8 and VAPB are potential diagnostic markers for cancer. Overall, understanding the role of MAM proteins in cancer provides insights into their potential as diagnostic and therapeutic targets.