Surreal illustration representing the search for biomarkers in lung cancer treatment.

PD-L1 Testing in Lung Cancer: Are We Chasing the Wrong Target?

Avery Sinclair in Health & Wellness December 2025 • 4 min read.

"Unraveling the complexities of PD-L1 as a biomarker for NSCLC treatment and exploring more reliable alternatives for personalized immunotherapy."

Immunotherapy, particularly treatments targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), has revolutionized the management of advanced non-small cell lung cancer (NSCLC). These therapies have become standard options in both initial and subsequent lines of treatment. While some patients experience lasting benefits, with 10-20% showing durable responses, identifying who will truly benefit remains a significant challenge.

PD-L1 expression, measured in tumor cells, has been used to predict responses to immune checkpoint inhibitors. However, its effectiveness as a biomarker has been inconsistent. Some studies show a correlation between PD-L1 levels and treatment success, while others do not. This inconsistency has led researchers to seek more reliable biomarkers to guide immunotherapy decisions.

This article examines the complexities of using PD-L1 as a biomarker in NSCLC, discusses the limitations that complicate its use, and explores promising alternative biomarkers currently under investigation. By understanding these challenges and emerging options, clinicians can move closer to personalized immunotherapy strategies for NSCLC.

Why PD-L1 Isn't Always the Answer: Understanding the Biomarker Puzzle

Surreal illustration representing the search for biomarkers in lung cancer treatment.

Several factors contribute to the challenges of using PD-L1 as a reliable biomarker:

Variability in testing:

Tissue Collection Timing: When the sample is taken can affect PD-L1 levels.
Antibodies and Methods: Different tests use different antibodies and scoring systems, leading to inconsistent results.
Test Design: Lack of standardized test designs makes comparing results across studies difficult.

The tumor microenvironment, including the presence of immune cells, can influence PD-L1 expression. It's not just about the cancer cells themselves, but also how they interact with the surrounding immune system.

Beyond PD-L1: The Future of Personalized Immunotherapy

While PD-L1 testing has limitations, research is actively exploring new and improved biomarkers to predict immunotherapy response. One promising avenue is tumor mutational burden (TMB), which measures the number of mutations in a tumor's DNA. Studies suggest that patients with high TMB may respond better to certain immunotherapies, regardless of their PD-L1 status.

Another approach involves analyzing gene expression signatures, which reflect the activity of different genes within the tumor and its microenvironment. These signatures can provide a more comprehensive picture of the tumor's immune landscape and predict response to specific treatments.

As research progresses, the integration of multiple biomarkers – including TMB, gene signatures, and potentially refined PD-L1 assessments – will likely lead to more personalized and effective immunotherapy strategies for NSCLC. The ultimate goal is to ensure that the right patients receive the right treatment at the right time, maximizing benefit and minimizing unnecessary side effects.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.21037/tlcr.2018.04.18, Alternate LINK

Title: Programmed Cell Death Ligand-1 (Pd-L1) As A Biomarker For Non-Small Cell Lung Cancer (Nsclc) Treatment—Are We Barking Up The Wrong Tree?

Subject: Oncology

Journal: Translational Lung Cancer Research

Publisher: AME Publishing Company

Authors: Wolfram C. M. Dempke, Klaus Fenchel, Stephen P. Dale

Published: 2018-09-01

Everything You Need To Know

How is PD-L1 used in non-small cell lung cancer (NSCLC) treatment decisions?

PD-L1 expression is assessed on tumor cells to predict how well someone might respond to immune checkpoint inhibitors in non-small cell lung cancer (NSCLC). However, it's not a perfect predictor. Some studies show a link between PD-L1 levels and treatment success, but others don't, leading to the search for more reliable biomarkers.

What are some of the reasons why PD-L1 testing can be unreliable?

Several factors make PD-L1 testing challenging. The timing of tissue collection, the use of different antibodies and scoring systems, and the lack of standardized test designs all contribute to inconsistent results. Also, the tumor microenvironment, including the presence of immune cells, can also influence PD-L1 expression.

What is Tumor Mutational Burden (TMB), and how does it relate to immunotherapy?

Tumor Mutational Burden, or TMB, measures the number of mutations in a tumor's DNA. Research indicates that patients with high TMB might respond better to certain immunotherapies, irrespective of their PD-L1 status. TMB offers a different perspective by looking at the genetic makeup of the tumor itself.

Besides PD-L1, what other types of biomarkers are being explored to predict immunotherapy response in NSCLC?

While PD-L1 focuses on a single protein's expression, TMB evaluates the overall genetic instability of the tumor. Gene signatures, analyze patterns of gene expression within the tumor and its microenvironment. These comprehensive approaches aim to capture a broader picture of the tumor's characteristics and its interaction with the immune system, potentially offering more accurate predictions of immunotherapy response.

What are the implications of PD-L1's limitations for the future of personalized immunotherapy in NSCLC?

The variability in PD-L1 testing and the complexity of the tumor microenvironment highlight the need for more comprehensive biomarkers like TMB and gene signatures. This shift aims to move towards personalized immunotherapy strategies that consider multiple factors beyond just PD-L1 expression. Future research will likely focus on combining these different biomarkers to create more accurate predictive models.