Therapeutic platforms for cancer management centered on blocking the PD-L1/PD-1 interaction through the use of aptamers: A review.

Envafolimab – novel anti-PD-1/PD-L1 antibody in cancer treatment

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.

PD-1+/PD-L1+macrophages across diseases: a translational continuum from biomarkers to immunotherapeutic targets.

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.

Anti-PD-1 single-chain variable fragments in cancer immunotherapy: from molecular engineering to clinical translation

Targeting PD-1/PD-L1 and CTLA-4 Immune Checkpoints for Therapeutic Advancement in Hepatocellular Carcinoma.

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.

Mechanisms underlying the failure of PD-1/PD-L1 blockade in glioblastoma: Therapeutic challenges and opportunities

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.

A Novel Dual-targeting PD-1 and TL1A Bispecific Antibody with Synergistic Effect for Immune Disorders Treatment 2255198

Programmed cell death protein 1 (PD-1), an inhibitory immune checkpoint on T cells, maintains immune homeostasis. Dysregulated PD-1 signaling is implicated in autoimmune pathogenesis, whereas insufficient activity may result in uncontrolled T-cell responses. TNF-like ligand 1A (TL1A), a member of the TNF superfamily, engages DR3 to activate NF-κB pathway, thereby amplifying pro-inflammatory cytokine production and contributing to chronic inflammation and fibrosis. We developed a novel bispecific antibody that co-targets PD-1 and TL1A to achieve synergistic inhibition of pathogenic immune activation, with relevance to both PD-1 and TL1A driven immune disorders. Bispecific antibodies were generated by fusing novel PD-1 agonistic and TL1A antagonistic VHH domains in a tetra-valent format. A series of candidates were evaluated through comprehensive in vitro assays including assessment of binding kinetics, PD-1/PD-L1/2 blocking, PD-1 agonism, TL1A-DR3 blocking, ADCC, and T-cell suppression. In vivo efficacy was assessed in a mouse colitis model. The leading bispecific antibody binds to a unique PD-1 epitope, enhances PD-1—PD-L1/2 engagement, and inhibits TL1A—DR3 binding. It demonstrated dose-dependent PD-1 pathway agonism and TL1A antagonism, suppressing T-cell activation, proliferation and cytokine production. Robust ADCC activity against PD-1+ T cells was observed. In vivo, it showed superior efficacy over comparator monotherapies in ameliorating colitis. The anti-PD-1xTL1A bispecific antibody exerts synergistic immunomodulation through three complementary mechanisms: enhancement of PD-1 inhibitory signaling, blockade of the TL1A—DR3 pathway, and selective depletion of PD-1-expressing T cells via ADCC. It significantly mitigates T-cell-driven inflammation in vitro and ameliorates disease activity in vivo, supporting its potential as a novel treatment for autoimmune diseases such as IBD (inflammatory bowel disease). Nanjing Leads Biolabs Co., Ltd Therapeutic Approaches to Autoimmunity (THER)