PD-1/PD-L1 blockade

Overview

PD-1/PD-L1 blockade refers to therapeutic inhibition of the programmed cell death protein 1 (PD-1) receptor and its ligand PD-L1, an immune checkpoint axis that normally restrains T-cell activation. In physiology, this pathway helps maintain peripheral immune tolerance and limits excessive inflammation. In cancer and some inflammatory settings, however, PD-1/PD-L1 signaling can be co-opted to suppress cytotoxic T-cell function, promote T-cell dysfunction, and support immune escape.

As a biomedical target, PD-1/PD-L1 blockade is most widely associated with immunotherapy, but recent studies also examine its role in non-oncologic immune dysregulation, including sepsis. Across these contexts, blockade of the pathway is investigated as a way to restore immune homeostasis, enhance anti-tumor immunity, and counteract immunosuppression. Related mechanisms in the recent literature include PD-L1-mediated suppression of cytotoxic CD8+ T cells, PD-1-associated T-cell dysfunction in multiple myeloma, and checkpoint modulation alongside pathways such as STAT3 and β-catenin.

Focus of Latest Publications

Recent investigations have focused on overcoming resistance to PD-1/PD-L1 blockade through rational combination therapies and temporal sequencing. Sequential treatment with axitinib (VEGFR inhibitor) followed by survivin vaccination and PD-1 blockade achieved high complete response rates in renal cell carcinoma by coordinating vascular reprogramming, antigen-specific priming, and checkpoint release. Intratumoral sodium bicarbonate combined with anti-PD-1 therapy (tislelizumab) in hepatocellular carcinoma elicited 93.3% objective response rate and exceptionally long median progression-free survival (31 months) by triggering immunogenic cell death and dendritic cell activation. Anti-CTLA-4 combined with PD-1 blockade prevented metastasis in immunotherapy-resistant pancreatic cancer by expanding CD4+ T cells with progenitor phenotype and restoring MHC-I expression. Chemical modulators synergized with checkpoint blockade across multiple malignancies: CDK1/Cyclin B1 inhibition in pancreatic cancer, EFHD2 inhibition in colorectal cancer, nanocrystalline berberine in ovarian cancer, and β-catenin palmitoylation inhibition in colorectal cancer each produced superior tumor control when combined with PD-1/PD-L1 blockade.

Mechanistic studies revealed that checkpoint inhibition paradoxically generates immunosuppressive cellular states limiting therapeutic benefit. PD-1/PD-L1 blockade enriched atypical regulatory T cells (AtpTregs) with reduced suppressive capacity but elevated IL-6 production, driving inflammatory arthritis; tocilizumab (anti-IL6R) alleviated this adverse effect while preserving antitumor immunity. PD-L1 blockade promoted immune evasion in pancreatic cancer through epigenetic silencing of Tap1, selecting for MHC-I-deficient tumor variants reversible by Treg depletion or anti-CTLA-4 therapy. Fibronectin-positive tumor-associated macrophages (FN1+ TAMs) mediated immunotherapy resistance in sarcomatoid renal cell carcinoma; FN1 blockade combined with anti-PD-1 reversed epithelial-mesenchymal transition programs and restored CD8+ T cell function. EFHD2-driven lactate metabolism similarly promoted M2 macrophage polarization and PD-L1 upregulation; targeting EFHD2 with checkpoint blockade synergistically enhanced radiosensitivity in colorectal cancer.

Engineered immunotherapeutics represent an emerging strategy for PD-1/PD-L1-directed treatment. SAR445877, a PD-1-targeted immunocytokine fusing anti-PD-1 antibody with detuned IL-15, delivered IL-15 signals specifically to PD-1+ T cells while blocking checkpoint interactions, enhancing T cell activation with reduced systemic inflammation. Bispecific VHH nanobodies achieved dual binding to PD-L1 and tumor antigens (EGFR, HER2) with single-digit nanomolar affinities. Nanoparticle platforms included artificial exosomes homing to neutrophils to simultaneously block PD-1/PD-L1 and promote neutrophil apoptosis during sepsis. These precision delivery systems aim to concentrate therapeutic activity while reducing off-target effects.

Peripheral blood biomarkers emerged as tools for predicting response and prognosis. In advanced cervical cancer, high baseline CD4+ percentage, elevated post-treatment CD8+ T cells, and reduced PD-1 expression on circulating T cells predicted treatment response and overall survival. Blood-based kinase activity profiling of peripheral mononuclear cells showed promise for predicting anti-PD-L1 response in non-small cell lung cancer. Exosomal biomarkers including PD-L1 expression on tumor-derived exosomes enabled dynamic monitoring of disease progression and therapeutic outcomes across treatment modalities.

Recognition of myeloid and tissue-resident immunoregulation has expanded understanding of checkpoint blockade effects. Myeloid-specific PD-L1 maintains cardiac homeostasis; its loss precipitated ICI-associated myocarditis, implicating myeloid PD-L1 as a therapeutic target for mitigating cardiotoxicity. In systemic lupus erythematosus, aberrant N-glycosylation of checkpoint molecules including PD-1 dysregulated T follicular helper cell differentiation. These studies collectively demonstrate that optimizing PD-1/PD-L1 blockade requires multi-faceted approaches targeting resistance mechanisms, leveraging biomarkers for patient stratification, developing engineered therapeutics with improved tissue targeting, and carefully managing adverse events.

Key Publications

• 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."
• NEWJun Treg cells promote immunotherapy-induced immune evasion by restraining CD4 T cell control of MHC-I-deficient metastatic pancreatic cancer. (Science immunology, 2026, PMID 42361199): "We demonstrate that programmed death-ligand 1 immune checkpoint blockade promoted immune evasion by epigenetic Tap1 (transporter associated with antigen processing 1) silencing, increasing selection of metastatic tumor variants with defective interferon-γ (IFN-γ)-inducible class I major histocompatibility complex (MHC-I) expression."
• NEWJun Sequential axitinib and survivin vaccination unlock curative PD-1 immunotherapy in renal carcinoma. (Oncoimmunology, 2026, PMID 42343214): "When PD-1 blockade is introduced concomitantly with vaccination, after, rather than during, axitinib treatment, the triple regimen (axitinib + [SVX + anti-PD-1]) achieves durable tumor control with a high rate of complete responses, outperforming all other treatment schedules."
• NEWJun Blood-based kinase activity profiling to predict response to immune checkpoint inhibitors in patients with advanced stage NSCLC: the prospective IOpener study. (Journal for immunotherapy of cancer, 2026, PMID 42342406): "The programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) is used as a biomarker to predict benefit from immune checkpoint blockade (ICB) in patients with non-small cell lung cancer (NSCLC)."
• NEWJan Nano-Immunotherapy Targeting TAMs: Precisely Regulating TAMs to Reverse Immunosuppressive TME. (International journal of nanomedicine, 2026, PMID 42333283): "...and blocking PD-L1 expression on TAMs."
• NEWJun Using peripheral blood indicators and T cells subsets to evaluate the efficacy of immunotherapy for advanced and recurrent cervical cancer. (Human vaccines & immunotherapeutics, 2026, PMID 42334275): "and PD-1 expression on T-cells using logistic regression (treatment efficacy，comparing 36 responders vs. 14 non-responders) and Cox regression (prognosis, with disease progression or death events occurring in 26 patients)."
• NEWJun EFHD2 drives lactate-mediated DNA damage repair and immunosuppression via HMGB1 and HIF-1α to confer radioresistance in colorectal cancer. (Cell death & disease, 2026, PMID 42336814): "Elevated EFHD2-driven lactate reshaped the tumor immune microenvironment by promoting M2 macrophage polarization, suppressing antigen presentation, activating nuclear factor kappa-B (NF-κB) signaling, and upregulating programmed death-ligand 1 (PD-L1)."
• NEWJun Programmed cell death protein 1 (PD-1) / programmed cell death ligand 1 (PD-L1) in multiple myeloma. (Journal of the Egyptian National Cancer Institute, 2026, PMID 42307688): "Among these, the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis contributes to T-cell dysfunction;"
• NEWJun Moxibustion combined with anti-PD-1 antibodies improves immunosuppression in septic mice potentially through the PD-1/PD-L1 pathway. (Immunologic research, 2026, PMID 42307810): "Combination therapy suppressed PD-1, PD-L1, and STAT3 expression in the spleen while reducing STAT3 nuclear translocation."
• Jun FN1+ macrophages fuel aggressive sarcomatoid differentiation and immunotherapy refractory outcome in clear cell renal cell carcinoma. (Oncogene, 2026, PMID 42249083): "Ex vivo functional assays using patient-derived tumors assessed the efficacy of FN1 blockade, as well as combination with PD-1 blockade."