Lung cancer remains the leading cause of cancer mortality worldwide, with an estimated 1.8 million deaths annually.

Conventional cytotoxic chemotherapy has historically yielded modest survival benefits with considerable toxicity.

The introduction of immunotherapy—specifically immune checkpoint inhibitors (ICIs)—has revolutionized therapeutic options, especially in non-small cell lung cancer (NSCLC), enabling durable responses in subsets of patients previously refractory to standard treatments.

Molecular Mechanisms Underpinning Immunotherapy

Tumor cells employ immune checkpoint pathways as immune evasion mechanisms. The PD-1 receptor, expressed on activated T cells, interacts with PD-L1 expressed by tumor cells and immune infiltrates, inducing T cell exhaustion and anergy. CTLA-4, primarily active in lymph nodes, attenuates T cell priming by competing with the co-stimulatory receptor CD28 for B7 ligands.

Blocking these inhibitory signals with monoclonal antibodies restores T cell effector function, unleashing cytotoxic activity against tumor cells. Importantly, the immunosuppressive tumor microenvironment (TME) of lung cancers, often enriched with regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and immunosuppressive cytokines (e.g., TGF-β, IL-10), poses additional barriers to effective immune responses.

Dr. Harish Patel, MD, PhD, an immuno-oncology expert at Memorial Sloan Kettering, emphasizes, "Understanding the dynamic interplay between tumor cells and the immune milieu is crucial for optimizing immunotherapeutic strategies. The heterogeneity of immune infiltration within lung tumors dictates response patterns to checkpoint blockade."

Clinical Trial Evidence and Current Indications

Clinical trials underpinning FDA approvals of ICIs have demonstrated significant survival improvements over chemotherapy in advanced NSCLC. KEYNOTE-024 showed pembrolizumab monotherapy improved median overall survival (OS) to 30 months in patients with PD-L1 TPS ≥50%, with a favorable toxicity profile compared to platinum doublet chemotherapy.

The CHECKMATE-227 trial revealed that combination nivolumab plus ipilimumab enhanced progression-free survival (PFS) in patients with high tumor mutational burden (TMB), independent of PD-L1 status. Despite these successes, response rates to ICIs range between 20-40%, underscoring the urgent need for better predictive biomarkers and combinatorial approaches.

Dr. Melissa Chang, MD, from MD Anderson Cancer Center, highlights, "Immunotherapy has shifted the treatment landscape, but patient selection remains imperfect. We must continue refining biomarker assays and investigating mechanisms of primary and acquired resistance."

Biomarker-Driven Patient Stratification: Challenges and Advances

PD-L1 expression detected via immunohistochemistry (IHC) remains the frontline biomarker guiding immunotherapy candidacy; however, intratumoral heterogeneity and temporal variability can lead to sampling errors and misclassification. Emerging biomarkers include circulating tumor DNA (ctDNA) profiles, neoantigen burden, and gene expression signatures indicating a T cell-inflamed phenotype.

TMB, defined as the total number of nonsynonymous somatic mutations per megabase, correlates with neoantigen generation and immune visibility. Nonetheless, standardization across sequencing platforms is lacking, complicating clinical implementation. Recent work by Dr. Anna K. Lee at Dana-Farber Cancer Institute proposes integrating multiplexed biomarker panels combining PD-L1, TMB, tumor-infiltrating lymphocytes (TILs), and gene signatures to refine patient stratification and guide treatment intensification.

Immune-Related Adverse Events (irAEs): Pathophysiology and Management

Checkpoint inhibitors can induce a spectrum of irAEs due to aberrant immune activation against normal tissues. Pulmonary toxicity, such as checkpoint inhibitor pneumonitis (CIP), is particularly concerning in lung cancer patients, with incidence rates ranging from 3-5% but mortality up to 20% in severe cases. Autoimmune endocrinopathies (thyroiditis, hypophysitis), dermatologic reactions, colitis, and hepatitis are also prevalent. The pathogenesis involves enhanced T cell reactivity, autoantibody production, and cytokine dysregulation.

Early recognition through vigilant clinical monitoring and imaging is essential. Immunosuppression with corticosteroids is first-line; refractory cases may require mycophenolate mofetil or infliximab. Ongoing research aims to identify predictive biomarkers for irAE risk to personalize monitoring and prophylaxis.

Novel Combination Strategies and Future Directions

To surmount resistance mechanisms—such as loss of antigen presentation, upregulation of alternative immune checkpoints (e.g., TIM-3, LAG-3), and immunosuppressive myeloid populations—combinatorial regimens are under active investigation. These include:

- Dual checkpoint blockade (e.g., anti-PD-1 plus anti-CTLA-4)

- Integration with targeted therapies against oncogenic drivers (EGFR, ALK)

- Combination with anti-angiogenic agents to normalize tumor vasculature and improve immune cell infiltration

- Incorporation of cancer vaccines, oncolytic viruses, and adoptive T cell therapies

Immunotherapy represents a transformative advance in lung cancer treatment, shifting the therapeutic paradigm from cytotoxic chemotherapy to immune modulation. Precision medicine approaches encompassing robust biomarker evaluation and multidisciplinary management of irAEs are essential to maximize patient benefit. Continued translational and clinical research will refine patient selection, overcome resistance, and expand immunotherapy's curative potential in lung cancer.