Jul 2026· Eurasian Journal of Medicine and Oncology· 0 citations
TL;DR
A dual-source PD-L1 framework is proposed to discuss the potential contributions of tumor cell-derived and immune cell-derived PD-L1 to GBM-mediated immunosuppression and therapeutic response and a multilayer resistance model involving the blood–brain barrier, an immunologically cold tumor microenvironment, and compensatory immunosuppressive networks is outlined.
Abstract
Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis and limited therapeutic options. Although programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade has transformed the treatment of several malignancies, its clinical benefit in GBM remains limited, and the mechanisms underlying this resistance remain poorly understood. This review summarizes the biological roles of the PD-1/PD-L1 axis in the GBM microenvironment, evaluates clinical evidence for immune checkpoint inhibitors, and discusses mechanisms of resistance and strategies to overcome therapeutic resistance. It integrates current preclinical and clinical evidence on PD-1/PD-L1 signaling, the cellular sources of PD-L1, clinical trial outcomes, resistance mechanisms, and emerging combination strategies. We propose a dual-source PD-L1 framework to discuss the potential contributions of tumor cell-derived and immune cell-derived PD-L1 to GBM-mediated immunosuppression and therapeutic response. However, whether these two PD-L1 sources have distinct functional specializations remains unproven and requires further validation through spatial omics analyses and cell-type-specific functional studies. This framework may help explain the limited value of total PD-L1 expression as a single predictive biomarker in GBM. We further outline a multilayer resistance model involving the blood–brain barrier, an immunologically cold tumor microenvironment, and compensatory immunosuppressive networks. Emerging strategies, including optimized treatment timing, microenvironmental modulation, and rational immunotherapy combinations, are also discussed. A deeper understanding of PD-1/PD-L1 biology and multilayered immune resistance may guide the development of more effective immunotherapeutic strategies for GBM.
Programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are critical immune checkpoints that dynamically maintain the balance between immune tolerance and immune activation. Immune checkpoint blockade targeting the PD-1/PD-L1 axis can restore T cell-mediated antitumor immunity and has shown remarkable clinical efficacy in the treatment of various solid tumors. However, owing to the complexity of the underlying mechanisms and the limitations of current predictive biomarkers, only a subset of patients derives durable benefit from this therapy. Although conventional paradigms have primarily regarded T lymphocytes as the main effectors of PD-1/PD-L1 signaling, accumulating evidence indicates that macrophages also play indispensable roles in shaping PD-1/PD-L1-mediated immunosuppressive tumor microenvironments, thereby extending the traditional understanding of this pathway. A deeper understanding of the functional roles and regulatory mechanisms of PD-1+/PD-L1+ macrophages in specific immune contexts is therefore essential for optimizing immunotherapeutic outcomes. In this review, we comprehensively summarize the regulatory mechanisms governing PD-1/PD-L1 expression in macrophages and their biological functions, and discuss the potential of PD-1+/PD-L1+ macrophages as prognostic biomarkers and therapeutic targets, and further examine targeted intervention strategies for this macrophage subset as well as their clinical diagnostic value.
Jinjing Wu, Dan Zhou, Kunpeng Jiang et al.· Biochemical Pharmacology· 0 citations
It is found that ICI monotherapy significantly improves overall survival in NSCLC with PD-L1 expression ≥50% compared with platinum-based chemotherapy, and first-line atezolizumab plus chemotherapy extended median overall survival to 12.3 months, compared with 10.3 months in extensive-stage SCLC.
Mojeeb Abdo Abdullah Qasem, T. Budhy, D. Suprabawati et al.· Health Dynamics· 0 citations
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, with limited effective treatments and a generally poor prognosis. Immune checkpoint pathways, particularly PD-1/PD-L1 and CTLA-4, play a crucial role in modulating the tumor microenvironment (TME) and facilitating immune escape in HCC. PD-1 is expressed on activated T cells, B cells, and macrophages, and interacts with PD-L1, which is often overexpressed on tumor cells and antigen-presenting cells. This interaction leads to T-cell inhibition and tumor immune evasion. Elevated PD-1/PD-L1 expression in HCC correlates with disease progression and poor outcomes. Inhibitors targeting PD-1 or PD-L1 have shown significant clinical benefits in some HCC patients, highlighting the therapeutic potential of this pathway. CTLA-4, another critical checkpoint molecule, negatively regulates immune responses by competing with CD28 for B7 binding on antigen-presenting cells, thereby dampening T-cell activation and proliferation. In HCC, CTLA-4 expression contributes to immune suppression and tumor growth. CTLA-4 blockade combined with PD-1/PD-L1 inhibitors has shown promise in enhancing anti-tumor immunity and improving clinical outcomes in HCC patients. The complex interplay between PD-1/PD-L1 and CTLA-4 pathways in HCC underscores the complexity of immune escape mechanisms. Targeting these checkpoints has the potential to reshape HCC treatment, offering hope for more effective and durable outcomes. Future research should focus on optimizing combination therapies, understanding resistance mechanisms, and identifying biomarkers for better patient stratification and response prediction. Advancements in this field could lead to more personalized and effective treatments, significantly improving the prognosis and quality of life for HCC patients.
K. Sharma, Hema Barti, Siddhant Jai Tyagi et al.· Current Gene Therapy· 0 citations
The landscape of immunotherapy in oncology has markedly advanced with the development of programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors, fundamentally reshaping cancer treatment by potentiating anti-tumor immune responses. PD-1/PD-L1 blockade agents, such as FDA-approved nivolumab, pembrolizumab, and dostarlimab, have demonstrated significant clinical efficacy across various malignancies. Additionally, investigational agents like envafolimab, a novel PD-L1 inhibitor, are currently under clinical evaluation for efficacy and safety in solid tumors. This review examines the emerging data on envafolimab and discusses strategies to optimize its therapeutic impact, including combination regimens and personalized approaches. Tailoring treatments based on individual genetic, immunological, and microbiome profiles holds the potential to enhance response rates and the durability of outcomes. The integration of these factors is pivotal in advancing the precision and success of immunotherapy in oncology.
M. Kciuk, D. Kołat, Katarzyna Wanke et al.· Frontiers in Immunology· 0 citations
Immune checkpoint inhibition has transformed the treatment of advanced non-small cell lung cancer (NSCLC), but primary and acquired resistance remain common. Vascular endothelial growth factor (VEGF) contributes to both tumor angiogenesis and immune suppression by promoting abnormal vasculature, limiting lymphocyte trafficking, and fostering an immunosuppressive tumor microenvironment. These complementary mechanisms provide a rationale for simultaneously targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and VEGF pathways. Bispecific antibodies integrating checkpoint blockade and VEGF neutralization within a single molecule have therefore emerged as a rapidly developing therapeutic strategy in NSCLC. Ivonescimab, a PD-1/VEGF bispecific antibody, currently has the most mature evidence, with randomized phase III trials demonstrating improvements in progression-free survival and, in selected settings, overall survival compared with established PD-1-based regimens. Other PD-1/VEGF agents, including PF-08634404, MK-2010, and JS207, have shown encouraging early activity but require randomized validation. Among PD-L1/VEGF bispecific antibodies, pumitamig, HB0025, and IMM2510 have demonstrated promising antitumor activity, although evidence is derived predominantly from early-phase or single-arm studies. Multiple phase III trials are evaluating these agents in first-line, post-immunotherapy, epidermal growth factor receptor (EGFR)-mutated, and stage III consolidation settings. VEGF-associated toxicities, including hypertension, proteinuria, hemorrhage, and thromboembolism, remain clinically relevant. Moreover, differences in checkpoint target, molecular architecture, target affinity, fragment crystallizable (Fc) engineering, pharmacokinetics, and VEGF-binding strategy preclude the assumption of a uniform class effect. The fixed bispecific configuration also prevents independent dose adjustment of the checkpoint and antiangiogenic components, which may complicate toxicity management. Mature randomized survival data, longer-term safety assessment, and biomarker development are needed to define optimal patient selection and the clinical role of PD-(L)1/VEGF bispecific antibodies in NSCLC.
Aleena Kuriakose, Salem Gogah, E. Beleva· Journal of Clinical Question...· 0 citations
Blocking the PD-1/PD-L1 (Programmed Cell Death Protein-1/Programmed Cell Death Ligand-1) pathway represents a pivotal approach in cancer immunotherapy, effectively promoting sustained antitumor immune responses while alleviating immunosuppressive mechanisms. Advancing novel technologies to enhance the efficacy of PD-1/PD-L1 blockade remains a critical focus in medical research. Nonetheless, challenges such as immune-related adverse effects, therapeutic resistance, and high treatment costs highlight the urgent need for innovative strategies that optimize clinical outcomes and accessibility. Aptamers are short, single-stranded oligonucleotides characterized by their high affinity and specificity for target molecules. Emerging as promising alternatives to traditional antibody-based therapies, they offer new avenues in cancer treatment. This review provides a comprehensive analysis of aptamer-driven strategies aimed at inhibiting the PD-1/PD-L1 immune checkpoint pathway. It summarizes recent advances in the design of PD-1/PD-L1-targeted aptamer systems and evaluates their potential to enhance therapeutic efficacy while addressing challenges related to immune resistance.
Abolfazl Marvizadeh, Elham Sameiyan, Amir Teymour Najjarkar et al.· International Journal of Bio...· 0 citations
