When mitochondria trigger an alarm: A study describes the link between tumour characteristics and anti-cancer immunity

A new publication in the journal Nature Communications shows that mechanical properties of breast carcinoma tissue can be linked to priming anti-cancer immune responses. A key role in the process is played by mitochondria DNA (mtDNA) that is, under certain circumstances, mobilized into the cytosol, presenting a warning signal. The study lead by Giorgio Scita from the University of Milan involved collaboration of Laboratory of Molecular Therapy, Institute of Biotechnology of the Czech Academy of Sciences at BIOCEV center.

Breast cancer is biologically a highly complex pathology. An important question of current research is the difference between individual tumours: while some tumours are immunologically active, others are immunologically inactive. They are also referred to as immunologically "hot" and "cold" tumours.

A new study uncovers how the immune activity of a tumour correlates with its physical and biological behavior. The premise here is that tumour tissue is not only a mass of fast-dividing cells but also presents dynamic environment in which cells change their movement, individual interactions, metabolism and relation to the immune system. Authors of the study focused on the process referred to as fluidization of tumour tissue. This reflects the state when malignant cells start to be more dynamic and the tumour less solid. Previous work by the team of Giorgio Scito reported that mechanical forces acting within a tumour can be linked with the activation of cellular defense mechanisms. The new paper brings into the picture the role of mtDNA.

The study shows that increased level of the RAB5A protein, being a result of movement of cancer cells, triggers cellular mechano-metabolic stress. This has an impact on mitochondria, i.e. subcellular structures essential for energy provision. Because of these changes, small pores form in the mitochondrial membrane composed of proteins BAX and BAK. These pores are used for translocation of mtDNA into the cytosol, where it is perceived as a warning signal. This triggers the activation of the immunogenic cGAS/STING pathway, which promotes inflammatory and interferon response.

The main contribution of this study is combination of several separate phenomena: mechanical properties of tumour tissue, alterations in mitochondrial structure, liberation of mtDNA and priming of the immune system. In other words, the research indicates a novel route resulting in promotion of a particular form of immune "alarm" by changes in physical behavior.

An essential component of the research are models of cancer cells lacking mtDNA, which was instrumental to show that immune response is not triggered in mtDNA absence, providing unequivocal evidence for the phenomenon. Molecular Therapy Laboratory of Institute of Biotechnology, CAS, contributed to this part of the study. Authors of the publication state that tumours with increased level of the RAB5A protein in the immunocompetent mice grew slower and contained higher number of immune cells, and that they showed higher vulnerability towards immunotherapy targeting immune checkpoint proteins. These results concern experimental conditions and are yet to be translated into clinical practice.

Concerning further research, this work points to the need of deeper understanding of the relationship between mechanical properties of tumour tissue, mitochondria and immune responses, and their impact on the search for better approaches on how to modulate antitumour immunity. It is believed that this and subsequent research will pave the way to clinical translation of the research for the benefit of oncological patients.

Publication:
Palamidessi A., Frittoli E., Corada M. et al. Mechano-metabolic feedback connects tissue fluidity to mitochondrial DNA–dependent immunity in breast cancer. Nature Communications, 2026.