programmed cell death 1

Overview

Programmed cell death 1 (PD-1) is an immune checkpoint receptor encoded by the PDCD1 gene and expressed primarily on activated T cells. It plays a central role in maintaining peripheral immune tolerance by dampening T-cell activation after engagement with its ligands, especially Programmed Death-Ligand 1 (PD-L1) and PD-L2. Through this inhibitory signaling axis, PD-1 helps limit excessive immune responses, but it can also be exploited by tumour cells and other suppressive elements of the tumour microenvironment to evade immune destruction.

Clinically, PD-1 has become a major therapeutic target in oncology. Antibodies such as pembrolizumab, nivolumab, cemiplimab, and camrelizumab block PD-1 signaling and can restore antitumour T-cell activity. However, response is variable, resistance is common, and treatment can cause immune-related adverse events. Recent research has therefore focused on PDCD1 genetic variation, combination strategies with CTLA-4 or LAG-3 blockade, radiotherapy, and mechanisms of T-cell dysfunction involving regulatory T cells, dendritic cells, cytotoxic T cells, and pathways such as CXCL-CXCR2 and TGF-β/VEGF.

Focus of Latest Publications

Recent publications on programmed cell death 1 (PD-1) largely focus on its role as a therapeutic target in cancer immunotherapy and on factors that shape response or resistance to PD-1 blockade. Several studies evaluated PD-1-directed treatment in combination regimens, including pembrolizumab-based therapy in metastatic lung adenocarcinoma and advanced non-small-cell lung cancer, camrelizumab as adjuvant therapy after hepatectomy for hepatocellular carcinoma, and PD-1 blockade combined with radiotherapy, chemotherapy, lenvatinib, or other immunomodulatory approaches. These reports collectively emphasize that PD-1 inhibition remains a central component of modern cancer treatment, but its efficacy is highly context dependent and often improved by rational combination strategies.

A recurring theme is resistance to anti-PD-1 therapy and the search for mechanisms that can restore sensitivity. In hepatocellular carcinoma, WNK4 was reported to promote tumor progression and anti-PD-1 resistance through exosome-mediated effects on cancer-associated fibroblasts and cysteine metabolism. In non-small-cell lung cancer, PKC signaling was implicated in resistance to PD-1 blockade, with studies showing that PKC inhibition could reduce immunosuppression, enhance CD8+ T-cell recruitment and function, and resensitize tumors to checkpoint therapy. Another study identified a PKC-XIAP axis as a regulator of immune resistance and suggested that PKC inhibition may work particularly well with anti-CTLA-4 in PD-1-refractory settings. Additional work linked GSK-3 to CD4-CD8 cooperation and showed that GSK-3 inhibition could synergize with PD-1 blockade to enhance cytolytic T-cell activity.

Other publications explored ways to potentiate PD-1 blockade by remodeling the tumor microenvironment or by using engineered delivery systems. Examples include low-dose radiotherapy combined with PD-1 blockade to promote antitumor neutrophil programming in advanced NSCLC, lenvatinib plus pembrolizumab to reduce immunosuppressive macrophages in gastric cancer, and engineered biohybrids or nanoparticles designed to block the PD-L1/PD-1 axis while enhancing immune activation. A remotely activated trans-vaccenic acid-based lipid nanoparticle platform was reported to reduce PD-1 levels in T cells and improve PD-L1 blockade therapy, while other studies used PD-1-modified membrane-camouflaged nanoparticles or PD1-expressing engineered bacteria to support tumor targeting and immune modulation.

Several papers also addressed PD-1 biology, biomarkers, and safety. One study examined temperature-dependent motions of the PD-1 N-terminal loop and their effect on nivolumab binding affinity, showing reduced complex stability at higher temperature. Another evaluated single nucleotide polymorphisms in the PDCD1 gene in pembrolizumab-treated metastatic lung adenocarcinoma, and a separate study assessed early pembrolizumab plasma levels as a prognostic biomarker in real-world NSCLC patients. In parallel, case reports and reviews highlighted immune-related adverse events associated with PD-1 inhibitors, including autoimmune hemolytic anemia, optic neuritis, and severe myasthenia gravis with myocarditis, underscoring the need for careful monitoring during checkpoint inhibitor therapy.

Key Publications

• NEWJul Immune checkpoint inhibitor-induced myasthenia gravis and myocarditis: a fatal immune-related adverse event. (Immunologic research, 2026, PMID 42384108): "By inhibiting proteins such as programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), these agents enhance the immune response against cancer cells."
• NEWJun Toward Nano-Nutritional Medicine: A Remotely Activated Trans-Vaccenic Acid-Based Lipid Nanoparticles for Enhancing Immune Checkpoint Blockade Therapy. (Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026, PMID 42261893): "...but downregulates PD-1 levels in T cells and upregulates PD-L1 levels in tumor cells..."
• NEWJun WNK4 Enhances Anti-PD-1 Resistance and Promotes Tumor Progression in Hepatocellular Carcinoma by Reprogramming Cysteine Metabolism in Cancer-Associated Fibroblasts. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42253146): "Immunotherapy, particularly targeting immune checkpoints such as programmed cell death protein 1 (PD-1), has shown considerable therapeutic promise."
• Jun Therapeutic bacteria-trained NK cells confer long-term protection against cancer metastasis. (Molecular therapy : the journal of the American Society of Gene Therapy, 2026, PMID 42237539): "stNK cells significantly outperform conventional immune checkpoint therapies, including PD-1 and TIGIT blockade, in preventing metastasis, underscoring the unique immunological mechanisms in combating metastasis."
• Jun Targeting XIAP-coordinated PKC signaling resensitizes PD-1-refractory tumors for rechallenge. (Proceedings of the National Academy of Sciences of the United States of America, 2026, PMID 42234523): "PD-1/PD-L1-directed immune-checkpoint blockade (ICB) is limited by primary or acquired resistance that is routinely countered-without mechanistic clarity-by empiric rechallenge."
• May Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy in advanced squamous non-small-cell lung cancer (HARMONi-6): interim overall survival analysis of a randomised, double-blind, phase 3 trial in China. (Lancet (London, England), 2026, PMID 42218899): "Bispecific antibodies targeting programmed death 1 (PD-1) and vascular endothelial growth factor (PD1-VEGF) have shown promising efficacy in non-small-cell lung cancer (NSCLC)."
• May Sacituzumab tirumotecan plus pembrolizumab versus pembrolizumab in PD-L1-positive advanced non-small-cell lung cancer (OptiTROP-Lung05): interim analysis of a randomised, open-label, phase 3 trial. (Lancet (London, England), 2026, PMID 42214392): "Sacituzumab tirumotecan (sac-TMT), a trophoblast cell-surface antigen 2-targeting antibody-drug conjugate, combined with programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors, has shown promising antitumour activity as first-line therapy for non-small-cell lung cancer (NSCLC) in early-phase studies."
• Jul Temperature Dependent Motions of N-Terminal Loop in PD-1 Determine the Affinity Towards Nivolumab. (Journal of molecular recognition : JMR, 2026, PMID 42199044): "Programmed Cell Death-1 receptors on the surface of monocytes and T and B cells modulate various immune responses and are key immunotherapy targets."
• May GSK-3 regulates CD4-CD8 cooperation for super-armed CD8+ cytolytic T cells in immunotherapy against tumors. (Signal transduction and targeted therapy, 2026, PMID 42156357): "GSK-3 inhibition and reduced expression synergized with PD-1 blockade to 'super-arm' cytolytic CD8⁺ T cells, characterized by upregulation of perforin and seven distinct granzymes."
• Jun Early pembrolizumab plasma levels as a prognostic biomarker in real-world NSCLC patients. (Pharmacological research, 2026, PMID 42097413): "Although approved dosing regimens achieve near-maximal PD-1 receptor occupancy in clinical trials, variability in pembrolizumab exposure in real-world scenario may influence outcomes."