Reprogramming the tumor microenvironment in mesothelioma: from immune suppression to therapeutic opportunity

Pleural mesothelioma (PM) is a rare and aggressive cancer with limited treatment options and poor prognosis. Unlike other thoracic cancers responding well to immunotherapy, PM typically lacks key predictive biomarkers such as Programmed Death-Ligand 1 (PD-L1) tumor expression. Nonetheless, immune checkpoint inhibitors (ICIs) have shown clinical activity in PM, particularly in non-epithelioid subtypes. However, only a subset of patients benefits from this approach, and resistance remains a major challenge. A growing body of evidence suggests that tumor microenvironment (TME) plays a central role in shaping this resistance. In PM, the TME is notably immunosuppressive, dominated by regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. These elements act as a shield against immune activation, limiting the efficacy of ICIs. Novel therapeutic strategies aimed at depleting or modulating suppressive immune populations within the TME are emerging as promising avenues to overcome resistance and enhance the effectiveness of ICIs. In this narrative review, we examine the unique features of the TME in PM, its role in immunotherapy resistance, and emerging strategies aimed at harnessing or remodeling the TME to improve patient outcomes.