Marta Iozzo1, Giuseppina Comito1, Luigi Ippolito1, Giada Sandrini2, Elisa Pardella1, Erica Pranzini1, Mariaelena Capone3, Gabriele Madonna3, Paolo Antonio Ascierto3, Paola Chiarugi1, Elisa Giannoni1. 1 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy 2 Institute of Oncology Research (IOR), Università della Svizzera Italiana (USI), Bellinzona, Switzerland 3 Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131, Naples, Italy AbstractMelanoma incidence and mortality are higher in male patients than female ones, likely associated to the sex dimorphism in immune responses. Pro- and anti-tumor immune immunity are altered by the metabolic changes occurring in the tumor microenvironment.Here, we identified the lactate dehydrogenase A (LDH-A), the key enzyme deputed to the lactate production, as a crucial metabolic player discriminating sex-related melanoma immune responses both in in vitro and in patient-derived specimens. Specifically, LDH-A-associated higher lactate secretion in male melanoma cells leads to a significant enrichment in pro-tumoral regulatory T cells (Treg) with a decrease in the number and activity of anti-tumor CD8+ T cells. Remarkably, pharmacological and genetic impairment of LDH-A in male melanoma cells are able to phenocopy female ones in terms of Treg and CD8+ infiltration. In keeping, in vivo pharmacological targeting of LDH-A in melanoma-bearing male mice significantly impairs tumor growth and lung colonization, and this correlates with a concomitant modulation of Treg and CD8+ T cells infiltration. Taken together, our findings underline sex-related differences in the melanoma LDH-A-promoting immune reshaping and suggest LDH-A targeting as an effective strategy to abolish the sex-gap in melanoma progression.