PD-1/PD-L1 Cancer Immunotherapeutics Reshape Tumor Microenvironment – Clinical Evidence and Molecular Mechanisms for AI-based Precision Medicine

PD-1 (Programmed cell death protein 1) located on T cells, binds to PD-L1 (Programmed cell death ligand 1) on cancer cells, to suppress T cell activation and enable immune evasion. Hitherto, reviews have mainly highlighted the role of PD-1/PD-L1 in anti-cancer immunomodulation, anti-cancer therapy resistance, and immune-related adverse events. However, there are critical modes of enhancement of therapeutic efficacy, which remain underappreciated. This review provides a holistic perspective on: (a) a comprehensive analysis of recent clinical trials targeting PD-1/PD-L1, specifically on the use of immune checkpoint inhibitors (ICIs); (b) the underlying molecular mechanisms of immune surveillance; (c) the role of ubiquitin-mediated post-translational modifications (PTMs, viz the ubiquitin machinery); and (d) the gut microbiome crosstalk with the PD-1/PD-L1 axis, which influences the tumor microenvironment (TME). Clarity gained from opinions exerted from these four factors, in this review, will provide insights on improving cancer prevention, diagnosis, and treatment, thus bridging translational research to the clinic. These standpoints will be presented with a view to advocating the integration of precision medicine with AI, to accelerate the discovery of more effective ICIs and enhance mono-/combinatorial drug strategies for PD-1/PD-L1-targeted therapy. Altogether, this review opines that AI-driven analytics will provoke an innovative impact on promoting clinical outcomes beneficial for cancer patients.