Targeting tumor mitochondria to enhance immunotherapy effectiveness

Solid tumors have ways to evade the immune system, fostering tumor growth and reducing the effectiveness of immunotherapies. T cells detect cancer cells and release interferon-gamma, a powerful cytokine (signaling molecule) that inhibits tumor growth. However, interferon-gamma alone has a limited effect in many cancers and its variable impact is not well understood.

Scientists at St. Jude Children’s Research Hospital found that removing a single protein from tumors could help thwart cancer cells in multiple ways, enhancing immunotherapy effects.

The study, published in Nature, shows that some cancer cells use the mitochondrial protein voltage-dependent anion channel 2 (VDAC2) as a “signal jammer” to block communication between tumor cells and the body’s anticancer defenses mediated by the immune system, revealing an unexpected central role for mitochondria in coordinating immune signaling. Removing VDAC2 increased cancer cell death in the presence of interferon-gamma and made tumors more recognizable to the immune system, rendering them more susceptible to multiple forms of immunotherapy.

“Despite the curative potential of immunotherapy, many patients still don’t respond to it,” said corresponding author Hongbo Chi, PhD, Department of Immunology chair. “We discovered a very potent way to enable cancers to be more responsive to immunotherapy by targeting proteins with dual protective roles in the tumor.”

The researchers identified VDAC2 using a CRISPR-Cas9 screen targeting metabolism-related genes in cancer cells. They exposed cancer cells to interferon-gamma or T-cell treatment to identify genes whose absence reduced tumor growth or increased T-cell activity. Removing VDAC2 from tumors had a profound effect, drastically increasing sensitivity to immunotherapies in previously resistant mouse models of skin, colon, and liver cancers.

With those initial results, the researchers investigated how VDAC2 protects tumors from immunotherapy. They found that the protein impedes interferon-gamma signaling in tumor cells, limiting activation of pro-apoptotic regulators and reducing tumor cell sensitivity to immune-mediated cell death. However, when the scientists removed VDAC2, interferon-gamma interacted better with the tumor cells, triggering cell death pathways. Moreover, inhibiting VDAC2 caused tumor cells to release inflammatory molecules called type I interferons, which activate the adaptive immune system. Both increased cell death and type I interferon production contributed to the markedly increased sensitivity of VDAC2-deficient tumor cells to immunotherapy.

Unexpectedly, the communication block within cancer cells was coming from mitochondria, which have their own unique DNA. As cellular powerhouses, mitochondria coordinate growth and death signals related to energy production. When cancer cells lacked VDAC2, interferon-gamma could disrupt mitochondria, causing them to release mitochondrial DNA and trigger type I interferon production by activating the cytosolic DNA–sensing pathway. The mitochondria also release the molecule cytochrome c, which activates cell death pathways, causing some tumor cells to self-destruct.

This study highlights VDAC2 as a promising therapeutic target and may inform future immunotherapy strategies for cancers that have been largely resistant to such treatments, including pediatric solid tumors. While no drugs currently exist, the findings could lead to the development of inhibitors targeting VDAC2 or components of its signaling pathway.