Unveiling the myxofibrosarcoma tumor microenvironment: implications for immunotherapy

Cecilia Profumo¹Massimiliano Grassi²Valentina Rigo¹Matteo Mascherini¹Paola Monti¹Giorgia Arcovito¹Giorgia Anselmi¹Laura Damele¹Giorgia Timon¹Danila Comandini¹Michela Croce^3*

• ¹IRCCS Ospedale Policlinico San Martino, Genoa, Italy
• ²IRCCS Humanitas Research Hospital Cancer Centre, Rozzano, Italy
• ³Unità Bioterapie, IRCCS Ospedale Policlinico San Martino, Genoa, Italy

Myxofibrosarcoma (MFS) is a rare and aggressive soft tissue sarcoma characterized by high genomic instability, resulting in high local recurrence rates and limited effective therapeutic options in advanced stages. Recent progress in cancer immunology research has encouraged investigation into the Tumor Microenvironment (TME) of sarcomas, including MFS, to identify immune-related biomarkers of prognostic and therapeutic relevance. Although data remain limited in MFS, existing evidence suggests a heterogeneous immune landscape, including: i) variable expression of immune checkpoint molecules such as Programmed Cell Death Protein 1 (PD-1) and Programmed Death-Ligand 1 (PD-L1), ii) presence of tumor-infiltrating lymphocytes, iii) alterations in antigen presentation pathways, and iv) a pronounced angiogenic signature. These findings underscore the potential role of immune biomarkers for patients' clinical stratification and the consequent possibility of developing new immunotherapeutic strategies. This review will focus on the cellular and molecular architecture of immune infiltration, vascular remodeling, and lymphoid neogenesis, assessing their prognostic and predictive value as potential biomarkers. Finally, we will present ongoing clinical trials aimed at modulating the immune-vascular niche to inform innovative therapeutic strategies for this challenging sarcoma subtype.