Immunotherapy Strategies for Non-Small Cell Lung Cancer Management

Non-small cell lung cancer (NSCLC) has historically carried a poor prognosis, but the advent of immunotherapy has transformed its management. Central to current strategies are immune checkpoint inhibitors (ICIs) that target regulatory pathways such as programmed death-1 (PD-1), programmed death-ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). By releasing inhibitory signals on T cells, these agents can elicit durable antitumour responses in a subset of patients. Adoptive cell therapies—encompassing chimeric antigen receptor T cells (CAR-T), T-cell receptor (TCR) engineered cells and tumour-infiltrating lymphocytes (TILs)—have shown early promise in clinical trials, although optimal targets and safety profiles remain under refinement. Therapeutic cancer vaccines, notably those based on patient-specific neoantigens, aim to prime the immune system against tumour-specific mutations. Combinatorial approaches pairing ICIs with chemotherapy, radiotherapy or targeted small-molecule inhibitors address both the immunogenic release of tumour antigens and the modulation of the tumour microenvironment. Biomarker-driven patient selection—using PD-L1 expression, tumour mutational burden (TMB) and mismatch-repair status—enhances response prediction, though heterogeneity in assays poses challenges. Mechanisms of primary and acquired resistance, including immune escape through neoantigen loss or suppressive stromal elements, are active areas of investigation. Overall, integrating immunotherapy into multidisciplinary care has improved survival outcomes and quality of life for many patients with advanced NSCLC, with ongoing efforts to extend benefits to earlier disease settings and to refine strategies for resistant tumours.

Research from Nature Portfolio

Recent studies have applied phylogenetic tracking combined with personalised neoantigen vaccination in epidermal growth factor receptor (EGFR)-driven NSCLC. By sequencing tumour clones before and after treatment with EGFR tyrosine kinase inhibitors and a bespoke somatic-mutation vaccine, researchers observed selective loss of vaccine-targeted neoantigens in progressing metastases. This immune escape was linked to chromosomal instability and a hostile microenvironment with low chemokine expression and elevated immunosuppressive macrophages. Analysis of pre- and post-whole-genome-doubling mutations highlighted the importance of selecting clonal neoantigens present at higher copy number to minimise antigen loss during metastatic progression. These findings emphasise the need for dynamic monitoring of tumour evolution and guide the rational design of more robust personalised vaccines in NSCLC.

Immunotherapy Strategies for Non-Small Cell Lung Cancer Management publication trend

The graph below shows the total number of articles in immunotherapy strategies for non-small cell lung cancer management across all publications each year (not limited to Nature Index journals).

Technical terms

Immune checkpoint blockade: Inhibition of regulatory pathways that limit T cell activation, enhancing antitumour immunity.

Neoantigen: A peptide derived from tumour-specific somatic mutations, capable of eliciting T cell responses.

Tumour microenvironment: The ensemble of immune, stromal and vascular cells surrounding a tumour, influencing response to therapy.

Tumour mutational burden: The total number of somatic mutations per coding region of a tumour genome, correlating with neoantigen load.

Adoptive cell therapy: Infusion of autologous or engineered immune cells with specific antitumour reactivity.

References

1. Lung cancer immunotherapy: progress, pitfalls, and promises. Molecular Cancer (2023).
2. Clonal driver neoantigen loss under EGFR TKI and immune selection pressures. Nature (2025).
3. Atezolizumab in Combination With Carboplatin and Nab-Paclitaxel in Advanced Squamous NSCLC (IMpower131): Results From a Randomized Phase III Trial. Journal of Thoracic Oncology (2020).
4. Cancer biomarkers: Emerging trends and clinical implications for personalized treatment. Cell (2024).