The paradox of breast cancer: the more it spreads, the more vulnerable it is to attack by the immune system

Breast cancer remains the most common cancer in Italia and the most frequently diagnosed among women, with an estimated 53,000 new cases each year. Thanks to screening programmes, an increasing proportion of cases is detected at a very early stage: this is the case with ductal carcinoma in situ (DCIS), which alone accounts for over 20 per cent of diagnoses. DCIS poses one of the most delicate challenges in breast cancer care: in most cases it remains benign, but in some patients it can progress to invasive cancer. At present, there are no tools capable of distinguishing with certainty between the two possible outcomes, and this poses a real risk of overtreatment.

It is against this backdrop that a new study conducted by researchers from IFOM and the University of Milan, supported by the AIRC Foundation and published in the journal *Nature Communications*, has been carried out. The paper, entitled “Mechano-metabolic feedback connects tissue fluidity to mitochondrial DNA–dependent immunity in breast cancer”, was coordinated by Giorgio Scita, head of the Mechanisms of Tumour Cell Migration laboratory at IFOM ETS – The AIRC Institute of Molecular Oncology, and a full professor in the Department of Oncology and Haematological Oncology (DIPO) at the University of Milan. The first authors of the article, who contributed equally to the research, are Andrea Palamidessi, Emanuela Frittoli and Monica Corada.

One of the least explored aspects of tumour progression concerns movement: not so much the molecular biology of the individual cell, but rather the way in which it moves through the tissue. Some cancer cells do not advance on their own, but move together, in a coordinated manner, like a flock of birds or a school of fish. This idea had already been partially demonstrated by the same research team in a previous study published in 2023 in *Nature Materials*, which had attracted the attention of the national media. Today, this line of research is enriched by a new finding: the collective movement that makes breast cancer cells more ‘fluid’ and invasive may also make them more recognisable to the immune system.

At the heart of this mechanism lies the Rab5A protein, which Scita’s team had previously identified as a regulator of the ‘fluidisation’ of tumour tissue. When Rab5A is more active, cells that are normally trapped within a compact mass regain their mobility and begin to move collectively. It is as if the tumour were changing from a solid to a fluid state, much like an ice cube that melts and expands.

This transformation, however, comes at a price. In order to become more fluid and mobile, the tumour tissue is subjected to severe mechanical and metabolic stress, which affects the mitochondria – the cell’s powerhouses – altering their shape and function. Mitochondria that are damaged but not completely destroyed release small amounts of mitochondrial DNA into the cytoplasm, a part of the cell where this genetic material would not normally be found.