Checkpoint inhibitors have transformed lung cancer treatment — but many patients still don’t respond. Why not?
Lung cancer immunotherapy relies on the immune system’s ability to detect and destroy tumour cells. At the centre of this response are CD8+ T cells, also called cytotoxic T lymphocytes (CTLs). These immune cells recognise cancer-specific markers, become activated, migrate into the tumour microenvironment, and selectively kill cancer cells. This T cell biology has driven the development of key treatments, including checkpoint inhibitors, cancer vaccines, and other T cell–based immunotherapies.
However, while these strategies are based on strong science, many have failed to deliver durable responses in large patient populations. Understanding why some lung cancer immunotherapies are ineffective and what’s being explored in clinical trials to overcome these challenges is key to improving future treatment outcomes.
How does Immunotherapy treatment for lung cancer work?
Your immune system has special cells called CD8+ T cells (also known as “killer” T cells). These cells are designed to find and destroy cancer cells, but cancer can sometimes block or weaken the process. Immunotherapy helps by boosting or restoring this natural immune response.
How the immune response works
- Finding the cancer: Immune cells detect abnormal proteins, called antigens, on cancer cells.
- Training the T cells: These antigens are taken to nearby lymph nodes, where CD8+ T cells are ‘trained’ to recognise and attack the tumour.
- Targeting the tumour: Trained T cells travel through the bloodstream to the tumour and kill the cancer cells.
- Boosting the attack: T cells send out signals to recruit more immune support and keep the attack going.
Where things go wrong
Cancer has clever ways of hiding from or suppressing the immune system. It can stop immune cells from being trained, block them from reaching the tumour, or wear them down once they arrive.
How immunotherapy helps
Treatments like checkpoint inhibitors and cancer vaccines were designed to overcome these roadblocks — giving T cells a better chance to do their job. But many of these early strategies haven’t delivered consistent results in clinical trials. That’s why attention is now shifting toward new approaches that engage the immune system in different and more effective ways.
The goal of treatment
To create a strong, lasting immune attack on cancer — without damaging healthy tissue. Scientists are now combining different strategies to improve how well this works in lung cancer.
The CD8+ T cell response: Orchestrating the immunotherapy response
A successful anti-tumour immune response depends on three key steps, all of which must go right for CD8+ T cells to kill cancer cells effectively. To understand why immune checkpoint inhibitors don’t always work, it helps to break down the CD8+ T cell response into three key phases.
Priming in the lymph node
Naïve CD8+ T cells are activated by antigen-presenting dendritic cells that deliver three signals:
- Signal 1: Tumour antigen presentation on MHC class I.
- Signal 2: Co-stimulation (e.g., CD28–CD80/86), required to avoid anergy.
- Signal 3: Cytokines (e.g., IL-12, type I IFNs) that guide differentiation into cytotoxic effectors.
CD4+ T cells enhance this priming by licensing dendritic cells via CD40–CD40L interactions.
Migration to the tumour microenvironment
Activated CTLs migrate to the tumour, guided by chemokines and vascular signals. Their ability to enter the tumour microenvironments depends on endothelial integrity and the presence of suppressive signals (e.g., VEGF, TGF-β).
Effector function at the tumour site
Once at the tumour, CTLs form immunological synapses with antigen-expressing cancer cells, release perforin and granzyme B, and secrete pro-inflammatory cytokines (e.g., IFN-γ, TNF-α) that sustain and amplify the anti-tumour response.
T cells recognise tumour antigens presented by MHC molecules on antigen-presenting cells (APCs) via their T cell receptors (TCRs). For full activation, they also require co-stimulation through CD28 binding to CD80/CD86 on the APC. CTLA-4, a checkpoint receptor on activated T cells, competes with CD28 for these ligands, delivering an inhibitory signal that dampens T cell activation. Anti-CTLA-4 antibodies (e.g., ipilimumab) block this signal and enhance T cell priming.
In the tumour microenvironment, activated CD8⁺ T cells upregulate PD-1. Binding of PD-1 to PD-L1 (expressed on tumour cells or antigen-presenting cells) inhibits T-cell function. Anti-PD-1 antibodies (e.g., pembrolizumab, cemiplimab, nivolumab) and anti-PD-L1 antibodies (e.g., atezolizumab, durvalumab) block this checkpoint interaction, restoring T-cell activity and relieving tumour-induced immunosuppression.
Lung Cancer Immunotherapy: Why It Doesn’t Always Work
Checkpoint inhibitors work by taking the brakes off the immune system, but they only work if the immune system knows there’s something to fight in the first place. For CD8+ T cells to mount an effective anti-tumour response, several steps need to go right. Unfortunately, cancer has evolved to sabotage many of them. Here are three of the biggest barriers:
Poor T cell priming and activation
CD8+ T cells are only activated and expanded when they ‘see’ fragments of cancer proteins (antigens) displayed on the surface of cells via MHC class I molecules. However, many tumours fail to present these antigens effectively or disrupt other components of T cell priming such as co-stimulation.
T cell exclusion in ‘cold’ tumours
Even if the CD+T cells are effectively primed, some tumour microenvironments are ‘cold’, meaning they lack CD8+ T cell infiltration.
T cell exhaustion and suppression in the tumour microenvironment
Some tumour microenvironments are ‘hot but suppressed’. They contain T cells that are either exhausted or actively suppressed through checkpoints.
In all cases, the T cell response is ineffective; however, the underlying biology and treatment strategies differ.
How have clinical trials addressed resistance to immune checkpoint inhibitors in lung cancer?
Below is a summary of the key immune resistance challenges and the recent clinical trial approaches.
Immune Resistance Mechanism | Description | Clinical Trial Strategies |
|---|---|---|
The Tumour Doesn’t Present Recognisable Antigens (Poor Immunogenicity) | Tumours with low tumour mutational burden (TMB) or weak neoantigens fail to activate dendritic cells, preventing CD8+ T cell priming. | · Cancer vaccines presenting tumour-associated antigens · Oncolytic viruses infecting tumour cells to release neoantigens and stimulate immunity · STING agonists mimicking danger signals to activate dendritic cells · T cell costimulation agonists targeting OX40, 4-1BB, CD27 |
T Cells Can’t Reach the Tumour (Poor Infiltration or “Cold” Tumours) | Tumours create a hostile “cold” microenvironment via low chemokines, stromal barriers, and abnormal blood vessels that exclude activated T cells. | · Chemokine modulators (e.g., CXCR3, CCR5) to attract T cells · Anti-VEGF agents combined with immunotherapy to normalise vasculature and improve infiltration · Dual checkpoint inhibitors (e.g., PD-1 + LAG-3, TIGIT) to convert “cold” tumours into “hot” ones |
T Cells Are
Suppressed or
Exhausted in the
Tumour
Microenvironment | Functional impairment of T cells due to suppressive cells (Tregs, MDSCs), immunosuppressive cytokines (TGF-β), and chronic stimulation causing exhaustion. | · Next-generation checkpoint inhibitors targeting LAG-3, TIM-3, TIGIT to reinvigorate exhausted T cells · TGF-β inhibitors to reduce immunosuppression |
The next chapter in lung cancer immunotherapy
Early enthusiasm for targeting immune checkpoints such as LAG-3, TIM-3, and TIGIT stemmed from their role in T cell exhaustion and immune suppression. However, clinical trials testing these dual checkpoint inhibitor combinations have not always delivered meaningful improvements beyond existing PD-1/PD-L1 therapies, with several companies abandoning their clinical development. Niche products continue to be examined in clinical trials.
Immune resistance also continues to be tackled in current and upcoming clinical trials using different approaches:
- Bispecific antibodies physically bring T cells into close proximity with tumour cells, bypassing poor antigen presentation and reinvigorating dysfunctional T cells.
- Antibody-drug conjugates (ADCs) deliver potent cytotoxic agents directly to tumours, enhancing cell kill while sparing normal tissue.
- Anti-VEGF agents (like bevacizumab) normalise tumour blood vessels and, among other effects, enhance immune cell infiltration and function
- Lung cancer vaccines aim to prime the immune system by improving presentation of tumour-specific antigens, especially in tumours with low mutational burden.
Interested in where lung cancer treatment is heading next?
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Additional resources
Khosla, A. A., Jatwani, K., Singh, R., Reddy, A., Jaiyesimi, I., & Desai, A. (2023). Bispecific Antibodies in Lung Cancer: A State-of-the-Art Review. Pharmaceuticals, 16: 1461. https://doi.org/10.3390/ph16101461
Lahiri, A., Maji, A., Potdar, P.D., Singh, N., Parikh, P., Bisht, B., Mukerjee, A., Paul, M. (2023) Lung cancer immunotherapy: progress, pitfalls, and promises. Mol Cancer 22, 40. https://doi.org/10.1186/s12943-023-01740-y
Stanley, R.; Flanagan, S.; Reilly, D.O.; Kearney, E.; Naidoo, J.; Dowling, C.M. (2023) Immunotherapy through the Lens of Non-Small Cell Lung Cancer. Cancers, 15, 2996. https://www.mdpi.com/2072-6694/15/11/2996
Zhao, S., Zhao, H., Yang, W., Zhang, L. (2025) The next generation of immunotherapies for lung cancers. Nat Rev Clin Oncol, 22, 592 https://doi.org/10.1038/s41571-025-01035-9
