Immunotherapy resistance and strategies in malignant pleural mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) remains one of the most aggressive thoracic malignancies, characterized by profound resistance to conventional modalities such as surgery, chemotherapy, and radiotherapy, resulting in persistently poor survival outcomes. The advent of immune checkpoint inhibitors (ICIs) has fundamentally reshaped the therapeutic landscape of MPM. Notably, dual programmed cell death protein 1 (PD-1)/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade has demonstrated superior efficacy over monotherapy in multiple phase I/II trials and has been established as a novel first-line standard of care. Nevertheless, the high incidence of resistance continues to pose a major clinical challenge. This therapeutic bottleneck is largely attributed to the unique biology of MPM, including a profoundly immunosuppressive tumor microenvironment, aberrantly activated signaling pathways, and complex metabolic reprogramming, which together form a multilayered defense network against immune attack. In response to this intricate resistance architecture, recent research efforts have increasingly focused on the development of precision combination strategies. By rationally integrating ICIs with anti-angiogenic agents, chemotherapy, metabolic modulators, and next-generation cellular immunotherapies [e.g., chimeric antigen receptor T cells (CAR-T), chimeric antigen receptor-natural killer (CAR-NK)], these approaches aim to dismantle immune evasion barriers and reinvigorate antitumor immunity. Concurrently, the discovery of novel biomarkers and their integration with multi-omics data are enabling more precise patient stratification, signaling the advent of an era of personalized immunotherapy for MPM. This review provides a systematic synthesis of the latest clinical advances and fundamental breakthroughs in MPM immunotherapy, with a particular focus on dissecting the multifactorial mechanisms underlying therapeutic resistance. Its core contribution lies in constructing a forward-looking framework for next-generation treatment strategies. It critically evaluates the translational potential of emerging approaches, including arginine deprivation therapy for argininosuccinate synthase 1 (ASS1)-deficient tumors, CAR-T cells, T-cell receptor fusion constructs, and oncolytic virotherapy. By integrating these innovative modalities with biomarker-guided patient selection, this review delineates a roadmap for transitioning MPM management from empirical therapy toward precision immuno-oncology, with the ultimate goal of achieving durable disease control in this challenging malignancy.

Keywords

Malignant pleural mesothelioma / immunotherapy / resistance to immune checkpoint inhibitors / tumor microenvironment

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