To date, glioblastoma remains, among adult brain tumours, the most aggressive and most treatment-resistant form. The poor efficacy of the available therapeutic options is due to the biological characteristics of this tumour's microenvironment. Extensive cell heterogeneity, severe hypoxia, i.e. oxygen deficiency, and immunosuppression render even the most recent therapeutic approaches ineffective.

The study, published in the international journal ‘Cancer Discovery’ with the participation of the Department of Experimental Medicine at Sapienza University of Rome, unravelled the mechanism by which neutrophils expressing the transferrin receptor (CD71) modify their metabolism in hypoxic tumour areas. The metabolic change of these cells enhances their immunosuppressive capacity, thus facilitating glioblastoma progression.

In particular, the hypoxic environment induces CD71+ neutrophils to produce more lactate. This metabolite is responsible for the lactylation of histones, proteins that interact with DNA, and the consequent production of arginase-1, an enzyme that contributes to blocking the anti-tumour T-lymphocyte response. The study showed that blocking histone lactylation reduces the immunosuppressive function of CD71+ neutrophils, slowing tumour growth.

This molecular process seems to be particularly relevant in supporting immunosuppression in glioblastoma. The same Sapienza-Wistar research group had, in fact, described in a previous paper that lactylation increases the suppressive capacity of GLUT1+ macrophages infiltrating the tumour microenvironment

‘Our work,’ says Aurelia Rughetti, coordinator of the Sapienza team, ‘underlines how the functionality of tumour-infiltrating immune cells is finely regulated at the epigenetic level by histone lactylation. Interfering with this molecular process, which affects both CD71+ neutrophils and GLUT1+ macrophages, may translate into an effective therapeutic strategy to reduce immunosuppression, counteract tumour resistance mechanisms, and enhance the efficacy of target therapy and immunotherapy'.

Alessio Ugolini, Fabio Scirocchi and Angelica Pace, alumni of the Network Oncology and Precision Medicine PhD programme, coordinated by Aurelia Rughetti and Marianna Nuti of the Department of Experimental Medicine and clinicians Luca D'Angelo and Antonio Santoro of the UOC of Neurosurgery of the Policlinico Umberto I General Hospital, participated in the project.

References:

Ugolini A, De Leo A, Yu X, Scirocchi F, Liu X, Peixoto B, Scocozza D, Pace A, Perego M, Gardini A, D'Angelo L, Liu JKC, Etame AB, Rughetti A, Nuti M, Santoro A, Vogelbaum MA, Conejo-Garcia JR, Rodriguez PC, Veglia F. Functional reprogramming of neutrophils within the brain tumor microenvironment by hypoxia-driven histone lactylation. Cancer Discov. 2025 Feb 28. doi: 10.1158/2159-8290.CD-24-1056

Further Information

Aurelia Rughetti

Department of Experimental Medicine, Sapienza University of Rome

aurelia.rughetti@uniroma1.it