Programmed Death-Ligand 1

Overview

Programmed Death-Ligand 1 (PD-L1), also known as CD274, is a cell-surface immune checkpoint protein that plays a central role in regulating T cell activity. By engaging programmed cell death 1 (PD-1) on activated T cells, PD-L1 transmits inhibitory signals that reduce T cell proliferation, cytokine production, and cytotoxic function. This pathway is an important physiological mechanism for limiting excessive immune activation, but it is also frequently co-opted by tumors to evade immune surveillance.

In cancer biology, PD-L1 is widely studied as a marker and mediator of immune escape. Its expression on tumor cells and cells within the tumor microenvironment can suppress cytotoxic T cell responses and influence sensitivity to immunotherapy. As a therapeutic target, PD-L1 is clinically relevant in the context of PD-1/PD-L1 axis blockade, and its expression is often used to help guide treatment decisions in several malignancies, including lung cancer, head and neck squamous cell carcinoma, colorectal cancer, hepatocellular carcinoma, and ovarian cancer.

Focus of Latest Publications

Recent publications have continued to position PD-L1 as a central marker and mechanistic node in tumor immune escape, treatment response, and resistance. In non-small-cell lung cancer (NSCLC), one study reported that PD-L1 is a reliable biomarker for predicting immunotherapy efficacy in patients without driver gene mutations, reinforcing its use in selecting patients for first-line immunotherapy. Another NSCLC-focused clinical analysis examined oncogene-driven disease and highlighted differential responses to targeted agents and immune checkpoint inhibitors, underscoring that PD-L1 interpretation may depend on molecular context.

Several studies linked PD-L1 expression to resistance or sensitivity across tumor types. In head and neck squamous cell carcinoma, hypoxia was reported to upregulate the MSC-AS1/ITGA5 axis and increase VEGFA/PD-L1 expression, suggesting a hypoxia-associated immunosuppressive program that requires direct experimental validation. In colorectal cancer, OVOL2 deficiency increased glycolysis, lactate production, and histone lactylation at the CD274 promoter, thereby upregulating PD-L1 and promoting CD8+ T-cell exhaustion. A separate colorectal cancer study found that circulating glycocholic acid-regulated signaling potentiated immune checkpoint therapy, with glycocholic acid promoting tumor PD-L1 expression and suppressing CD8+ T-cell-mediated antitumor immunity.

Multiple reports focused on therapeutic strategies that reduce PD-L1 expression or block its function. In triple-negative breast cancer, celastrol was described as inhibiting immune escape and proliferation through the LKB1–AMPK–PD-L1/MYC signaling pathway. In hepatocellular carcinoma, phenethyl isothiocyanate downregulated PD-L1 in a concentration-dependent manner and increased sensitivity to T cell-mediated cytotoxicity, with ZNF652 implicated in PD-L1 regulation. In cervical cancer, alpelisib reduced PD-L1 (CD274) expression in PI3Kα-mutant models, alongside effects on HPV16 E7, YAP1, and EGFR. In Merkel cell carcinoma models, dual inhibition of HIF-2α and MEK reduced PD-L1 expression and promoted immunogenic remodeling, including increased calreticulin exposure.

PD-L1 was also studied in the context of combination immunotherapy. A phase 3 trial in PD-L1-positive advanced NSCLC evaluated sacituzumab tirumotecan plus pembrolizumab versus pembrolizumab alone, reflecting ongoing efforts to improve outcomes in PD-L1-selected populations. In metastatic lung adenocarcinoma, pembrolizumab outcomes were discussed in relation to PD-L1 expression, and in resectable locally advanced head and neck squamous cell carcinoma, perioperative pembrolizumab plus standard of care was noted in the context of FDA approval for PD-L1 CPS ≥ 1 disease. In advanced rare cancers, PD-L1 combined positive score ≥10 was associated with pembrolizumab biomarker enrichment, although responses also occurred in biomarker-negative tumors.

Beyond conventional antibody therapy, PD-L1 has been used as a targeting handle for engineered platforms. A PD-L1-targeted radioligand was integrated with protein degradation for precision tumor theranostics, and a bifunctional CPG2-anti-PD-L1 fusion protein was designed to combine tumor targeting with enzyme-mediated prodrug activation. Another study used a PD-L1-targeting peptide ligand to engineer artificial platelet injection system constructs for targeted protein degradation. Aptamer-based extracellular vesicle phenotyping systems also included PD-L1 among the markers recognized for specific detection.

Several studies examined PD-L1 in immune microenvironment engineering and immune evasion. A PD-1-presenting nanoemulsion blocked PD-L1 on tumor cells and enhanced uptake, while a PD-1 protein expressed on biohybrids was reported to inhibit immune evasion by blocking the PD-L1/PD-1 pathway. In dendritic cell extracellular vesicles, eliminating PD-L1 potentiated immune-mediated tumor rejection in mice, indicating that PD-L1 can also be functionally relevant on therapeutic vesicle platforms. In another study, STING agonism was limited by PD-L1 upregulation, motivating development of a bifunctional STING agonist/PD-L1 inhibitor. Similarly, pyroptosis-inducing nanomedicines were described as restoring responsiveness to PD-1/PD-L1-based immunotherapy in selected settings.

PD-L1 was also implicated in broader immune checkpoint biology. A study on checkpoint inhibitors reported treatment with PD-1, PD-L1, or CTLA-4 inhibitors in patients with cancer and described the emergence of rogue regulatory T cells. In multiple myeloma, the PD-1/PD-L1 axis was highlighted as a contributor to T-cell dysfunction. In NSCLC, protein kinase Cι-driven macrophage infiltration mediated immunosuppression, and the PD-1/PD-L1 axis was noted as a major therapeutic target despite frequent resistance. Additional work suggested that PD-L1 expression can be modulated by signaling pathways such as cAMP-PKA-CREB, and that DDX3 may control PD-L1 cell-surface presentation through 3' untranslated region-dependent mechanisms.

Outside oncology, PD-L1 was also investigated in atopic dermatitis, where rutin was reported to target PD-L1 based on network pharmacology and experimental evidence. Collectively, these studies reinforce PD-L1 as both a biomarker of immune suppression and a therapeutic target across cancer and inflammatory disease contexts.

Key Publications

• NEWJul Clinical implications of PD-L1 expression in oncogene-driven NSCLC: Differential responses to targeted agents and immune checkpoint inhibitors. (International journal of cancer, 2026, PMID 41872688): "PD-L1 is a reliable biomarker for predicting immunotherapy efficacy in NSCLC patients without driver gene mutations."
• NEWJul Engineered biohybrids for photothermally enhanced chemodynamic-immunotherapy through reprograming immunosuppressive microenvironment and inhibiting immune evasion. (Journal of colloid and interface science, 2026, PMID 41740575): "Furthermore, PD1 protein expressed on BLPC would inhibit immune evasion by blocking the programmed cell death ligand 1 (PD-L1)/PD1 pathway, further enhancing the immunotherapy."
• NEWJul Degradation-controlled synchronization of HIF-2α and MEK inhibition using self-sealed porous silicon nanoparticles to reprogram tumor immunogenicity. (Acta biomaterialia, 2026, PMID 42217661): "Sustained dual inhibition enhanced cytotoxicity and promoted immunogenic remodeling in MCPyV-negative Merkel cell carcinoma models, including increased calreticulin exposure and reduced PD-L1 expression."
• NEWJul A hypoxia-responsive migrasome-related lncRNA signature predicts prognosis and suggests the MSC-AS1/ITGA5 axis as a potential therapeutic target in head and neck squamous cell carcinoma. (Functional & integrative genomics, 2026, PMID 42380675): "Hypoxia upregulated the MSC-AS1/ITGA5 axis and increased VEGFA/PD-L1 expression, along with changes in the migrasome-related protein TSPAN4, suggesting a potential association with migrasome-related molecular features, which requires direct experimental validation."
• NEWJul Genome-wide variation in cell-free DNA end-motif entropy predicts immunotherapy response in head and neck cancer. (The Journal of clinical investigation, 2026, PMID 42154530): "...outperforming PD-L1 expression and tumor fraction in matched samples."
• NEWJul Checkpoint inhibitors create rogue regulatory T cells. (The Journal of clinical investigation, 2026, PMID 42383349): "...treatment with PD-1, PD-L1, or CTLA-4 inhibitors in patients with cancer."
• NEWJul Eliminating PD-L1 on Dendritic Cell Extracellular Vesicles for Immunotherapy Potentiates Immune-Mediated Tumour Rejection in Mice. (Journal of extracellular vesicles, 2026, PMID 42377985): "While PD-L1 expression on cancer-derived EVs has been shown to suppress immune responses, its role on immunotherapeutic EVs remains unexplored."
• NEWJul Integrating PD-L1-targeted radioligand with protein degradation for precision tumor theranostics. (Journal of controlled release : official journal of the Controlled Release Society, 2026, PMID 42372826): "Targeting programmed death ligand 1 (PD-L1) with proteolysis-targeting chimera (PROTAC) remains challenging due to the inability of visualized synergistic methods."
• NEWJun An Aptamer-Engineered Phenotyping System for Extracellular Vesicles Based on Honeycomb-like Melamine-Formaldehyde Microspheres and Carbon Dot Nanozymes. (Analytical chemistry, 2026, PMID 42296185): "Subsequently, iron-doped carbon dot nanozymes with high peroxidase-like activity were conjugated to aptamers targeting CD63, HER2, MUC1, and PD-L1, thereby providing specific recognition and colorimetric signal amplification."
• NEWJul Glucose and Lactate Cooperatively Deprived by a PD-1-Presenting Nanoemulsion for Potentiated Antitumor Immunotherapy. (ACS nano, 2026, PMID 42266067): "In detail, surface PD-1 proteins not only blocked PD-ligand 1 (PD-L1) on tumor cells but also promoted the cellular uptake of FGL@PM."