Programmed cell death 1 (PD-1)

Overview

Programmed cell death 1 (PD-1), also known as CD279 and encoded by the PDCD1 gene, is a cell-surface immunoinhibitory receptor of the immunoglobulin superfamily. It is expressed mainly on activated T cells, and also on B cells, natural killer cells, and other immune populations. Engagement of PD-1 by its ligands Programmed Death-Ligand 1 (PD-L1) and PD-L2 recruits phosphatases to the receptor's cytoplasmic tail, which dephosphorylate proximal T-cell receptor signaling components and attenuate T-cell activation, proliferation, and cytokine production. Physiologically, this inhibitory axis limits collateral tissue damage during immune responses and helps maintain peripheral tolerance; the same protein has been linked to autoimmune susceptibility, reflected in its alias "systemic lupus erythematosus susceptibility 2."

In cancer, tumour cells and suppressive elements of the tumour microenvironment — including regulatory T cells, macrophages, and cancer-associated fibroblasts — exploit PD-1 signaling to blunt cytotoxic T-cell and dendritic-cell-driven antitumour immunity, contributing to the exhausted T-cell states seen in progressive disease. Blocking this interaction is the basis of one of the central strategies in modern immuno-oncology: monoclonal antibodies such as pembrolizumab, nivolumab, cemiplimab, camrelizumab, and tislelizumab bind PD-1 and restore effector T-cell function, and small molecules that disrupt the PD-1/PD-L1 interface are under active development. These agents are used across many solid tumours, often combined with chemotherapy, radiotherapy, antiangiogenic agents such as lenvatinib, or blockade of other checkpoints including CTLA-4 and LAG-3. Responses remain heterogeneous, and PD-L1 expression measured by combined positive score or tumour area positivity is widely used to stratify patients, though it is an imperfect predictor. Resistance mechanisms involving stromal metabolic reprogramming and signaling through pathways such as TGF-β and VEGF, along with immune-related adverse events including colitis, hepatitis, endocrinopathies, myocarditis, and myasthenia gravis, define the major limitations of PD-1-directed therapy.

Recent Publications Summary (latest 30 papers)

Recent studies on programmed cell death 1 (PD-1) have continued to focus on its role as a therapeutic target in cancer immunotherapy, with several reports evaluating PD-1 blockade in combination regimens and in biomarker-defined patient subsets. In advanced HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, pooled individual patient-level analyses across multiple phase III trials found that adding a PD-1 antibody to chemotherapy improved overall survival in patients with intermediate PD-L1 expression, particularly those with 1 ≤ CPS < 10 and 1 ≤ CPS < 5, while benefit was not seen in CPS < 1 disease 42477829Jul. In advanced squamous non-small-cell lung cancer, interim analyses from randomized phase 3 studies evaluated PD-1-based combinations such as ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy, and sacituzumab tirumotecan plus pembrolizumab versus pembrolizumab, reflecting ongoing efforts to optimize first-line PD-1-directed treatment strategies 42218899May42214392May. A phase 1 study also reported on OSE-279, a high-affinity humanized anti-PD-1 monoclonal antibody, describing its safety, pharmacokinetics, and pharmacodynamics in patients with advanced solid tumors 42034003Apr.

Multiple preclinical and translational studies examined ways to enhance or overcome PD-1 blockade by combining it with agents that remodel the tumor microenvironment or tumor-intrinsic resistance pathways. Engineered bacteria expressing CXCL13 were designed to promote bladder cancer immunotherapy, and the abstract indicates that when combined with programmed cell death protein 1 targeting, this approach elicited germinal center responses in tumor-draining lymph nodes in mouse models 42485436Jul. A dual-target small molecule, B14, was developed to inhibit both the PD-1/PD-L1 interaction and NAMPT, enhancing T cell-mediated tumor killing and suppressing tumor progression in a mouse model 42366729Jun. Other studies reported that receptor-tethered cytosolic modulators could locally inhibit Src family kinases within the PD-1 microdomain, suppress PD-1 phosphorylation, and restore T-cell activity 42329051Jun. In addition, low-dose radiotherapy combined with PD-1 blockade produced durable survival in advanced NSCLC in a phase I trial and a real-world cohort, with mechanistic evidence pointing to neutrophil-dependent systemic antitumor immunity 42091852May. lenvatinib plus PD-1 blockade in gastric cancer was associated with reduction of immunosuppressive macrophages and improved antitumor immunity, while a bispecific anti-CHI3L1/anti-PD-1 strategy showed greater antifibrotic efficacy than monotherapy in pulmonary fibrosis models 42044259Apr42048160Apr.

Several publications addressed resistance to PD-1 therapy and the tumor or host factors associated with response. In hepatocellular carcinoma, WNK4 was reported to promote resistance to anti-PD-1 therapy by reprogramming cysteine metabolism in cancer-associated fibroblasts, and STK40 ablation or inhibition synergized with PD-1 blockade to drive tumor regression and T cell reinvigoration 42253146Jun42208540May. Another study identified PKC signaling as a therapeutic target in anti-PD-1-refractory tumors, showing that pan-PKC inhibition could overcome resistance through immunogenic pyroptotic cell death, PD-L1 degradation, and enhanced CD8+ T cell recruitment 42234523Jun. A separate report described GSK-3 as a regulator of CD4-CD8 cooperation for cytolytic T-cell responses in immunotherapy, supporting the broader concept that intracellular signaling pathways shape responsiveness to PD-1-directed treatment 42156357May. biomarker-focused work also included a multicenter prospective study of PDCD1 single-nucleotide polymorphisms in pembrolizumab-treated metastatic lung adenocarcinoma, and a real-world analysis of early pembrolizumab plasma levels as a prognostic marker in metastatic NSCLC 41965156Apr42097413May.

Beyond efficacy, recent publications also highlighted immune-related toxicities and other clinical considerations linked to PD-1 inhibition. Case reports and reviews described serious immune-related adverse events after PD-1 checkpoint inhibitor therapy, including autoimmune hemolytic anemia, myasthenia gravis, and myocarditis 41944848Apr42384108Jul. Another study reported an increased incidence of B-cell malignancies in patients with lung cancer receiving PD-1 blockade therapy, with evidence that PD-1 blockade activated PD-1-positive TFH cells in lymphoma tissue 42148884May. Structural and biophysical work showed that temperature-dependent motions of the PD-1 N-terminal loop altered affinity for nivolumab, suggesting that physiologic and pathophysiologic temperature changes can influence PD-1-antibody interactions 42199044May. Additional studies explored PD-1 in combination with other modalities, including PD-1 plus chemotherapy in mucosal melanoma trial design, PD-1-based imaging with 89Zr-labeled bispecific probes, and PD-1-centered combination immunotherapy in ovarian cancer preclinical imaging studies 41991257Apr42026833Apr41957244Apr.

What Changes, What Holds

1. PD-1 blockade appears most useful in biomarker-defined subsets rather than uniformly across all gastric cancer
REINFORCES Pooled trial analyses sharpen the baseline’s point that PD-1 benefit is heterogeneous and that PD-L1 testing is an imperfect but still useful stratifier. The new work does not overturn the established role of PD-1 antibodies in gastric and gastro-oesophageal junction cancer; it narrows where the survival gain is most credible, especially around intermediate PD-L1 expression, while leaving low-expression disease less convincing. 42477829Jul

2. Combination strategies remain the main route to improving PD-1 efficacy, but the best partner is still unsettled
REINFORCES These studies extend the baseline’s account of PD-1-directed therapy as a combination platform rather than a stand-alone solution. The important change is not a new biological role for PD-1, but the growing evidence that microenvironmental remodeling, radiotherapy, and dual-target approaches may deepen responses or overcome resistance. The comparative question is still open, and the interim nature of some data means practice should not move faster than validation. 42218899May42091852May

3. Resistance to PD-1 therapy is increasingly tied to tumor-stromal metabolism and intracellular signaling, but the mechanisms remain preclinical or early translational
NEW DIRECTION Work on WNK4, STK40, PKC, and related pathways adds specific resistance biology that the Overview did not cover, namely that non-immune tumor and stromal programs can actively rewire responsiveness to anti-PD-1 therapy. This does not contradict the established idea of resistance; it gives it new mechanistic depth and suggests additional targets for combination therapy. The biomarker studies also reinforce the need for better predictors of response, but they are not yet practice-changing. 42253146Jun42234523Jun

4. PD-1 inhibition carries broader clinical liabilities and assay considerations than the core immune toxicities already recognized
NEW DIRECTION The new reports expand the baseline’s adverse-event profile by adding autoimmune hemolytic anemia and a possible association with B-cell malignancies, while also showing that antibody binding can be temperature-sensitive. None of this displaces the established benefits of PD-1 blockade, but it does widen the safety and pharmacology discussion beyond colitis, hepatitis, endocrinopathies, myocarditis, and myasthenia gravis. The malignancy signal is especially unsettled and would need stronger causal evidence before altering surveillance or prescribing. 41944848Apr42148884May

Overview update candidates: biomarker refinement of benefit in gastric cancer; resistance mechanisms involving cancer-associated fibroblasts and intracellular signaling targets; rare hematologic toxicity signals and temperature-dependent antibody binding.