Inhibiting VDAC2 may enhance immunotherapy effectiveness

Research published today in Nature suggests that blocking a protein known as VDAC2 could enhance how tumors respond to immunotherapy. This study from St. Jude Children's Research Hospital reveals that some cancer cells utilize VDAC2 to act like a signal jammer. This jamming prevents effective communication between the body's immune system and its anticancer response. The findings show a significant role for mitochondria, the energy-producing parts of cells, in this process. In healthy individuals, T cells can detect and attack cancer cells by releasing a protein called interferon-gamma, which helps stop tumor growth. However, many cancers manage to escape the effects of this protein, limiting the success of immunotherapies. By removing VDAC2, researchers observed a marked increase in cancer cell death and more inflammation in tumors. This made the tumors more susceptible to different types of immunotherapy. The study points to the potential of developing treatments that inhibit VDAC2 and similar proteins that help tumors resist therapy. To identify the proteins that contribute to tumor resistance, scientists employed CRISPR-Cas9 technology. They modified cancer cells and tested them with interferon-gamma to see which proteins affected tumor growth. In experiments with mouse models of skin, colon, and liver cancers, removing VDAC2 significantly improved sensitivity to immunotherapies. Further investigations confirmed that VDAC2 restricts tumor cells from effectively receiving signals from the immune system. When VDAC2 was removed, tumor cells became more reactive to interferon-gamma, activating pathways that lead to cell death. Additionally, this change initiated a response that increased the release of inflammatory signals, enhancing the immune attack on the tumors. Researchers also found that mitochondria play a surprising role in this process. When VDAC2 was absent, mitochondria, which contain their own DNA, released this DNA and activated signaling pathways that contribute to antitumor immunity. This finding highlights the mitochondria's critical role in these immune responses. Currently, no specific drugs are available to inhibit VDAC2, but this study opens doors for future research. Targeting VDAC2 could help make tumors more vulnerable to immunotherapy and improve treatment effectiveness. The researchers emphasize the importance of focusing on signaling molecules that protect tumor cells in multiple ways for potential drug development.