Beyond PD-1/PD-L1: TME-Targeted Therapies in the Era of Immunotherapy Resistance
Keywords:
Tumor Microenvironment, Immunotherapy, Programmed Cell Death-1 Receptor, T-Lymphocytes, Myeloid-Derived Suppressor Cells, Extracellular MatrixAbstract
Blockade of PD-1/PD-L1 axis has revolutionized the cancer treatment, but clinical responses are often compromised by acquired resistance. Recent data suggested that tumor microenvironment (TME) is a key contributor of immunotherapy failure due to its ability to suppress immune reactions, place metabolic limitations, alter cytokine signaling, and extracellular matrix remodeling. This editorial identifies some of the TME-mediated resistance mechanisms and explains how new therapeutic approaches could be transformed beyond PD-1/PD-L1. Strategies such as myeloid cell reprogramming, regulatory T-cell regulation, metabolic therapy, neutralization of cytokines, targeting of extracellular matrix, and nanotechnology-mediated drug delivery are discussed as new promising perspectives in the context of immunotherapy resistance to restore antitumor immunity.
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Copyright (c) 2026 Asma Khawaja, Abdul Mannan Jehangir (Author)
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