Programmed Death-Ligand 1
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.