PD‑L1 importance in malignancies - comprehensive insights into the role of PD‑L1 in malignancies: from molecular mechanisms to therapeutic opportunities

Sep 23, 2026

Upregulated programmed death-ligand 1 (PD‑L1) expression is widespread across human malignancies and promotes immune evasion by engaging PD‑1 on activated T lymphocytes, disrupting anti‑tumour signalling. Beyond immune regulation, PD‑L1 can directly influence oncogenic programs, supporting tumour proliferation and survival. This dual role complicates the success of immune checkpoint inhibitors and positions PD‑L1 as a therapeutic target. The review integrates cancer cell–intrinsic signalling mechanisms linking PD‑L1 tumour expression to proliferation, cancer stem-like traits, immune modulation, DNA repair and transcriptional control. It synthesizes molecular foundations and clinical relevance across solid and haematological cancers to refine therapeutic strategies and improve outcomes.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Abstract

Introduction

Molecular structure and signalling pathways of PD‑L1 and PD‑1

Programmed death ligand‑1 (PD‑L1)

PD‑L1 expression and regulation

Clinical and Experimental Medicine (2025) 25:106 [https://doi.org/10.1007/s10238-025-01641-y](https://doi.org/10.1007/s10238-025-01641-y) PD‑L1 importance in malignancies comprehensive insights into the role of PD‑L1 in malignancies: from molecular mechanisms to therapeutic opportunities Mojdeh Soltani1 · Mohammad Abbaszadeh1 · Hamed Fouladseresht1 · Mark J. M. Sullman3,4 · Nahid Eskandari1,2 Received: 17 January 2025 / Accepted: 16 March 2025 / Published online: 3 April 2025 © The Author(s) 2025 Abstract The phenomenon of upregulated programmed death-ligand 1 (PD-L1) expression is common in numerous human malignancies. The overexpression of PD-L1 significantly contributes to immune evasion because its interaction with the PD-1 receptor on activated T lymphocytes impairs anti-tumour immunity by neutralizing T cell stimulatory signals. Furthermore, beyond its immunological interface, PD-L1 possesses intrinsic capabilities that directly modulate oncogenic processes, fostering cancer cell proliferation and survival. This dual function of PD-L1 challenges the efficacy of immune checkpoint inhibitors and highlights its possible application as a direct target for therapy. Recent discoveries concerning the cancer cell-intrinsic signalling pathways of PD-L1 have significantly enhanced our understanding of the pathological implications linked to its tumour-specific expression. These entail the orchestration of tumour proliferation and viability, maintenance of cancer stem cell-like phenotypes, modulation of immune responses, as well as impacts on DNA repair mechanisms and transcriptional regulation. This review aims to deliver an exhaustive synthesis of PD-L1's molecular underpinnings alongside its clinical implications in a spectrum of cancers, spanning both solid neoplasms and haematological disorders. It underscores the necessity for an integrated understanding of PD-L1 in further refining therapeutic strategies and improving patient outcomes. Keywords Programmed death ligand-1 · Solid tumour · PD-L1 · Immune checkpoints · Haematological malignancies · Immunotherapy Introduction Cancer cells adeptly utilize a variety of mechanisms to circumvent immune recognition and responses, thereby facilitating disease advancement and escalating patient mortality rates [1] . Among these immune-evasion tactics, the manipulation of immune checkpoints represents a critical * Nahid Eskandari[neskandari@med.mui.ac.ir](neskandari@med.mui.ac.ir) 1 Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran 2 Applied Physiology Research Center, Cardiovascular Research Institute, Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran 3 Department of Life and Health Sciences, University of Nicosia, Nicosia, Cyprus 4 Department of Social Sciences, University of Nicosia, Nicosia, Cyprus target for therapeutic innovation. Programmed cell death ligand-1 (PD-L1), also called B7-H1 or CD274, functions as an immune checkpoint ligand, naturally present in tissues including the placenta, lungs, and heart. In contrast, within malignancies, PD-L1 is overexpressed and binds to the PD-1 receptors on immune effector cells, which inhibits their activation and results in the suppression of antitumour immune responses [2] . PD-L1 expression is susceptible to upregulation by pro-inflammatory cytokines, notably Interferongamma (IFN-γ), secreted by activated T cells and natural killer (NK) cells. This regulatory process is instrumental in shaping the immune landscape of the tumour microenvironment [3] . In response, various immune checkpoint blockade (ICB) agents (e.g. anti-PD-1 and anti-PD-L1) have received FDA approval and have undergone extensive clinical trials targeting conditions including non-small cell lung cancer (NSCLC), bladder cancer, melanoma, Hodgkin’s lymphoma (HL), renal cell carcinoma (RCC), head and neck squamous cell carcinoma (HNSCC), and

FAQs

Why is PD‑L1 important in malignancies?

PD‑L1 is commonly upregulated in cancers and drives immune evasion by impairing PD‑1–mediated activation of T lymphocytes. It also has intrinsic tumour-promoting functions that support proliferation and survival.

How does PD‑L1 contribute to immune checkpoint inhibitor limitations?

Its dual role—both immune-interface modulation and direct oncogenic regulation—can reduce the overall efficacy of immune checkpoint inhibitors. This highlights PD‑L1 as a potential therapeutic target beyond checkpoint blockade.

What aspects does the review cover about PD‑L1?

It examines molecular underpinnings, including structural features, intracellular signalling pathways, transcription factors, and non-coding RNAs, and then connects these to clinical impact across solid and haematological cancers.

Sep 23, 2026

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