IIS La Fe study reveals how triple-negative breast cancer reprograms immune cells to promote lung metastasis

Triple-negative breast cancer can "educate" immune system cells to help prepare the way for lung metastasis. This is the main conclusion of a study led by researchers from the Translational Cancer Research Group at IIS La Fe and Hospital Universitari i Politècnic La Fe, published in the scientific journal OncoImmunology.

Metastasis is the leading cause of mortality in patients with triple-negative breast cancer, one of the most aggressive forms of breast cancer. This tumour subtype is characterised by the absence of hormone receptors and HER2, which limits targeted treatment options and is associated with a greater capacity for dissemination and relapse.

The tumour does not act alone: it modifies its environment

Until now, one of the major questions in cancer research has been how some tumour cells manage to survive their journey through the body and establish themselves in distant organs. This study provides an answer: the tumour does not act in isolation, but instead modifies cells in its surroundings and puts them to work for its own benefit.

Specifically, the researchers have observed that tumour cells "educate" macrophages and turn them into tumour-associated macrophages. Once reprogrammed, these macrophages release a set of cell-communication signals-including the cytokines and chemokines CCL3, CCL4, CXCL2 and IL-1β-that activate biological programmes in tumour cells, increasing their ability to migrate, cross the walls of blood vessels and subsequently establish themselves in the lungs.

In other words, triple-negative breast cancer manages to make cells that are part of the immune system contribute to creating an environment that is more favourable to tumour progression.

A dialogue that also weakens the anti-tumour response

The study also shows that this communication between the tumour and macrophages not only facilitates lung colonisation, but also contributes to creating a more permissive immune environment. Reprogrammed macrophages promote the emergence of regulatory T cells, a type of immune cell that can reduce the defensive response against the tumour and reinforce an immunosuppressive microenvironment.

María Rosado Sanz, the study's author, explained that "this finding helps explain why some triple-negative breast tumours display more aggressive behaviour and a poorer response to certain treatments". In fact, the study links the presence of immunosuppressive programmes and macrophages with a pro-tumour profile to a poorer response to neoadjuvant chemotherapy.

Blocking the message to halt colonisation

One of the study's most relevant contributions is that the researchers not only identified this communication between the tumour and macrophages, but also demonstrated that blocking it reduces several of the processes required for tumour dissemination.

To this end, they used inhibitors targeting different receptors involved in this communication-including maraviroc, navarixin and anakinra-and observed a reduction in tumour cell migration and lung colonisation in preclinical models.

Although these results still need to be validated in additional studies before clinical application, the research opens up a potential avenue for designing strategies aimed at preventing the tumour from preparing the ground for metastasis.

A new perspective on metastasis

The study provides a new perspective on cancer dissemination, suggesting that metastasis may depend not only on the intrinsic characteristics of tumour cells, but also on their ability to modify their surrounding environment and exploit immune system cells.

In the case of triple-negative breast cancer, where metastatic relapse remains one of the main clinical challenges, understanding these mechanisms is essential for developing more effective treatments and exploring future therapeutic combinations targeting the tumour microenvironment.

The research involved the Health Research Institute La Fe, Hospital Universitari i Politècnic La Fe, the University of Valencia, the National Centre for Genomic Analysis, the University of Barcelona and the Princess Máxima Center for Pediatric Oncology, among other collaborating institutions.

The research received support from the Association of Women Affected by Breast Cancer (AMACMA D8) of Requena, projects funded by the Ministry of Science, Innovation and Universities, the VLC-BIOMED 2024 programme of the University of Valencia and IIS La Fe, and predoctoral fellowships from the Scientific Foundation of the Spanish Association Against Cancer, Erasmus+ and the Generalitat Valenciana.