PD-1/PD-L1: The Core Pathway of Tumor Immune Checkpoint Inhibition and a New Paradigm for Lung Cancer Treatment

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This article focuses on the molecular characteristics and clinical value of the PD-1/PD-L1 immune checkpoint pathway, systematically elaborating the physiological function of PD-1 as a negative regulatory receptor on the surface of T cells in maintaining immune tolerance and the pathological mechanism by which tumors exploit it to achieve immune evasion, analyzing the therapeutic principle of PD-1/PD-L1 inhibitors in restoring T cell killing function by blocking this pathway, and discussing the efficacy and safety evidence as well as biomarker screening strategies for these inhibitors in first-line and second-line treatment of advanced lung cancer.

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PD-1/PD-L1: The Core Pathway of Tumor Immune Checkpoint Inhibition and a New Paradigm for Lung Cancer Treatment

Brief Introduction: Focusing on the molecular characteristics and clinical value of the PD-1/PD-L1 immune checkpoint pathway, this article systematically elaborates on the physiological function of PD-1 as a negative regulatory receptor on the surface of T cells in maintaining immune tolerance and the pathological mechanism by which tumors exploit it to achieve immune evasion, analyzes the therapeutic principle of PD-1/PD-L1 inhibitors in restoring T cell killing function by blocking this pathway, and discusses the efficacy and safety evidence as well as biomarker screening strategies in first-line and second-line treatment of advanced lung cancer.

I. The rise of tumor immunotherapy and the core position of immune checkpoints.

In recent years, tumor immunotherapy has emerged as a rising star in cancer treatment, standing out in the treatment of various cancers and becoming another powerful weapon after surgery, radiotherapy/chemotherapy, and targeted therapy. Therefore, the authoritative American journal Science selected tumor immunotherapy as the top of the ten major scientific and technological advances of 2013. Tumor immunotherapy, which utilizes the "switches" that control immune responses in the human body—immune checkpoints—has demonstrated broad application prospects in the field of tumor treatment. Currently, immune checkpoint inhibitors available for clinical use include CTLA-4 immune checkpoint inhibitors and PD-1/PD-L1 immune checkpoint inhibitors, among which the FDA has approved PD-1/PD-L1 immune checkpoint inhibitors for the treatment of lung cancer. This translation from a basic immunological concept to a clinical therapeutic approach marks a paradigm shift in tumor treatment from directly killing tumor cells to relieving immune suppression.

II. The molecular characteristics and physiological negative regulatory function of PD-1.

PD-1, known as programmed death protein-1, is a transmembrane receptor on T cells and was first obtained in apoptotic T cell hybridomas using subtractive screening. Under normal circumstances, PD-1 is a negative regulatory molecule for T cell proliferation and plays an important role in maintaining the body's immune tolerance. The value of this physiological function lies in preventing excessive activation of the immune system from causing damage to self-tissues—after PD-1 binds to its ligand, it inhibits excessive amplification of T cell receptor signaling, allowing the immune response to terminate appropriately after clearing pathogens. Therefore, PD-1 is not merely an "immune brake" but an indispensable regulatory node in the immune homeostasis maintenance system.

III. The mechanism by which tumors exploit the PD-1/PD-L1 pathway to achieve immune evasion.

Cunning tumor cells, in order to avoid being "eliminated" by the immune system, have evolved multiple escape mechanisms, one of which exploits the PD-1/PD-L1 signaling pathway. Under tumor and viral infection conditions, PD-L1 and PD-L2 expression is upregulated and interacts with the PD-1 receptor on the surface of T cells, thereby inhibiting T cell activation, proliferation, and killing of tumors, causing T cell dysfunction and exhaustion. In other words, when PD-L1 ligands expressed by malignant tumors bind to PD-1 molecules on the surface of lymphocytes, they weaken the body's anti-tumor immune response and promote tumor immune evasion. From a signaling mechanism perspective, after PD-L1 binds to PD-1, it recruits SHP-2 phosphatase, which dephosphorylates key kinases in the T cell receptor signaling pathway, thereby blocking downstream PI3K/AKT and RAS/MAPK signal transduction, ultimately leading to T cell proliferation arrest, reduced effector cytokine secretion, and loss of cytotoxic function. Tumor cells precisely through this mechanism convert T cells that should attack them into a functionally exhausted state.

IV. The mechanism of action of PD-1/PD-L1 inhibitors.

PD-1/PD-L1 immune checkpoint inhibitors block the PD-1/PD-L1 signaling pathway using monoclonal antibodies against PD-1 or PD-L1, restoring the immune killing function of T cells and thereby achieving good therapeutic effects. The core logic is that the binding of antibodies to PD-1 or PD-L1 spatially blocks the ligand-receptor interaction, relieving SHP-2 inhibition of T cell receptor signaling and enabling T cells to regain proliferative capacity and cytotoxic effector function. Unlike traditional chemotherapy, which directly kills all rapidly dividing cells, this strategy relies on the patient's own T cell functional reserve, so its efficacy is closely related to the infiltration status of immune cells in the tumor microenvironment and the level of PD-L1 expression.

V. Efficacy evidence of PD-1/PD-L1 inhibitors in advanced lung cancer.

Lung cancer, as the most common malignant tumor in China, ranks first in both incidence and mortality among patients, with both incidence and death numbers higher in male patients than in female patients. More seriously, early-stage lung cancer has an insidious onset with insignificant symptoms, resulting in approximately 75% of patients being diagnosed at an advanced stage. The latest SEER data show that the 5-year survival rate for patients with advanced non-small cell lung cancer is only 4.5%. With the outstanding clinical performance of PD-1/PD-L1 immune checkpoint inhibitors, new hope has emerged for the treatment of advanced lung cancer.

In terms of first-line treatment, clinical studies have confirmed that for patients with PD-L1 positive expression of no less than 50% and negative for EGFR and ALK mutations, first-line treatment with PD-1/PD-L1 immune checkpoint inhibitors, compared with traditional chemotherapy, increased the one-year overall survival rate from 54% to 70%, increased median progression-free survival from 6 months to 10.3 months, and reduced the incidence of severe adverse reactions from 53% with chemotherapy to 27%. In terms of second-line treatment, compared with chemotherapy, patients with squamous cell carcinoma treated with PD-1/PD-L1 immune checkpoint inhibitors had their median survival extended from 6 months to 9.2 months, with a 41% reduction in death risk and a decrease in the incidence of severe adverse reactions from 55% to 7%; for patients with non-squamous cell carcinoma, compared with chemotherapy, the death risk decreased by 27%, and the incidence of severe adverse reactions also decreased from 54% to 10%. It can be seen that PD-1/PD-L1 immune checkpoint inhibitors provide good survival improvement and favorable tolerability in the clinical treatment of various types of lung cancer.

VI. Conclusion.

As the most representative immune checkpoint pathway in tumor immunotherapy, PD-1/PD-L1 has become the core driving force transforming the treatment landscape of malignant tumors such as lung cancer, relying on the negative regulatory function of PD-1 in maintaining immune tolerance under normal physiological conditions, the immune evasion mechanism by which tumor cells upregulate PD-L1 to bind PD-1 and inhibit T cell activation and proliferation, and the therapeutic principle by which blocking antibodies relieve this inhibition and restore T cell killing function.

In basic research on the PD-1/PD-L1 pathway and the development of immunotherapeutic drugs, efficient and reliable binding activity detection tools are the core means for evaluating blocking antibodies and candidate molecules. TR-FRET technology, with its homogeneous operation, high signal-to-noise ratio, and direct reflection of antibody competitive binding, has become an ideal platform for evaluating PD-1/PD-L1 interactions. To meet the needs of PD-1/PD-L1 pathway research and immune checkpoint inhibitor development, UniOne provides the UniOne® TR-FRET Human PD1/PD-L1 Binding Kit. This product is suitable for applications such as quantitative analysis of PD-1 and PD-L1 binding activity, in vitro screening and activity evaluation of PD-1/PD-L1 blocking antibodies, determination of half-maximal inhibitory concentration of candidate molecules, and validation of the mechanism of action of immune checkpoint inhibitors.

This article is reviewed and published by the technical expert team of UA

Disclaimer: This article partially utilizes artificial intelligence assistance in its creation. If any content involves copyright or intellectual property issues, please let us know and we promise to verify and remove it as soon as possible.

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