Nickan Research Institute Immunopathologia Persa 2423-8015 12 2 2026 07 01 The role of immunogenomics in advancing precision immunotherapy for non-small cell lung cancer e43950 e43950 10.34172/ipp.2025.43950 EN Hamed Hekmat Nejad https://orcid.org/0000-0002-5716-9240 Fatemeh Nezhad Hossein Pooyan Kamalvand Seyed Ali Hosseini Mohsen Farrokhpour https://orcid.org/0000-0001-6057-5437 Journal Article 10.34172/ipp.2025.43950 2025 06 30 2025 12 06 Among lung cancers, the majority of cases are non-small cell lung cancer (NSCLC), which is the main causes of death is due to molecular complexity and comparative resistance to treatment. Immunogenomics has been able to provide a novel approach to developing targeted immune-based therapies by integrating high-throughput sequencing with immune profiling. The present study investigates the role of immunogenomics tools, including whole exome sequencing, RNA- sequencing, and single-cell analysis to identify tumor-specific mutations, neoantigens, and immune evasion mechanisms in NSCLC. Additionally in this study, key biomarkers including tumor mutation burden (TMB), microsatellite instability (MSI), and programmed death ligand-1 (PD-L1) expression are investigated for their predictive value in response to immune checkpoint inhibitors (ICIs). The development of personalized cancer vaccines, T-cell receptor-based therapies, and chimeric antigen receptor (CAR)-T cell approaches tailored to each patient’s genomic profiling and immunologic is enabled by immunogenomics. By reviewing clinical studies, we concluded that patients with high TMB as well as a strong neo-antigen load will show improved responses to ICIs. Integrated genomic analyses will lead to the emergence of new immune targets as well as resistance pathways, thus facilitating combination therapies. Immunogenomics links molecular findings with immune-based precision medicine, thereby defining a new therapeutic paradigm for the treatment of patients with NSCLC. Since we still face serious challenges such as tumor heterogeneity and data standardization, the use of immunogenomics in the context of treatment decisions, overcoming resistance, and improving patient survival outcomes in patients with NSCLC is of great importance.