The emergence of immunotherapy has dramatically altered this landscape. For the first time, durable responses and long-term survival are achievable for a meaningful proportion of patients, particularly those with advanced Non–Small Cell Lung Cancer (NSCLC) [2,3]. Lung cancer mainly breaks down into Non-Small Cell Lung Cancer (NSCLC) (most common: Adenocarcinoma, Squamous Cell Carcinoma) and Small Cell Lung Cancer (SCLC) (more aggressive), treated with surgery, chemo, radiation, but advanced care focuses on Targeted Therapies (blocking specific mutations like EGFR, ALK, ROS1) and Immunotherapy (PD-1/PD-L1 inhibitors like Pembrolizumab) for personalized, less toxic treatments, especially for advanced stages. It is known that Epidermal Growth Factor Receptor (EGPR), Anaplastic Lymphoma Kinase (ALK) , and ROS proto-oncogene 1 or c-ros oncogene 1 (ROS1) are all crucial genes/receptors often mutated or rearranged in cancers like non-small cell lung cancer (NSCLC) and effectively targeted by specific therapies.What distinguishes immunotherapy from earlier modalities is not only its ability to extend survival but also its biological paradigm: lung cancer is now understood within the complex interplay between malignant cells and the host immune system. This shift has unlocked a wave of biomedical innovation, advancing the oncological field far beyond the foundational success of Immune Checkpoint Inhibitors (ICIs).

Immunotherapy in Early-Stage Disease. One of the most significant advances is the extension of ICIs into earlier stages of lung cancer. Neoadjuvant immunotherapy has demonstrated higher rates of major pathological response (MPR) and improved surgical outcomes [4]. Adjuvant immunotherapy similarly reduces recurrence risk following complete resection, as shown in trials such as IMpower010 [5]. These studies reflect a philosophical shift toward treating micro-metastatic disease before it evolves into more resistant states.

Table 1. Main Lung Cancer Types and Descriptive Characteristics [5—10]

In the past six-seven years, extraordinary significant progresses were made in lung cancer treatment, due to the development of innovative and effective immunotherapy genes techniques, represented in Table 2.

Table 2. Advanced Treatment Approaches in Lung Cancer Therapy [4-11]

Novel immunotherapy for lung cancer effective treatment involves combining immune checkpoint inhibitors (ICIs) with chemotherapy, radiation, or targeted drugs, developing next-generation  therapies like bispecific antibodies (e.g., PD-L1 x TIGIT*) and CAR-T cells (Chimeric Antigen Receptor T-cells), and leveraging mRNA vaccines, all aimed at overcoming resistance and improving outcomes, especially for small cell lung cancer (SCLC) and challenging non-small cell lung cancer (NSCLC) cases, with a focus on personalized approaches using biomarkers[6-16].  PD-L1 x TIGIT refers to the combination or bispecific targeting of two immune checkpoint pathways: PD-L1 (Programmed Death-Ligand 1) and TIGIT (T cell immunoreceptor with Ig and ITIM domains), often used together in cancer immunotherapies to boost anti-tumor immunity by blocking both pathways simultaneously, enhancing T cell function against cancer cells [6-16]..

Key genetic markers for NSCLC mutations driving targeted treatments include EGFR, ALK, ROS1, BRAF, KRAS, MET, RET, HER2, and NTRK, often tested via Next-Generation Sequencing (NGS) on tumor tissue or blood (liquid biopsy) to match patients with specific therapies like TKIs, plus immune biomarkers like PD-L1 for immunotherapy. Common alterations involve EGFR mutations, ALK/ROS1/RET fusions, BRAF V600E, MET amplification/exon 14 skipping, KRAS mutations, and HER2 alterations, guiding personalized NSCLC care [5,6]. 

Essential Biomarkers used. Common Actionable Gene Mutations & Fusions are:

• EGFR (Epidermal Growth Factor Receptor): Common in non-smokers, often adenocarcinoma; mutations like Exon 19 deletions or L858R benefit from EGFR inhibitors (TKIs).
• ALK (Anaplastic Lymphoma Kinase): Rearrangements (fusions) leading to EML4-ALK are frequent in non-smokers; targeted by ALK inhibitors.
• ROS1 (ROS proto-oncogene 1): Gene fusions similar to ALK, also common in non-smokers (adenocarcinoma), targeted by ROS1 inhibitors.
• BRAF: The V600E mutation is a key target for BRAF/MEK inhibitors*. BRAF V600E mutation (B-Raf proto-oncogene, serine/threonine kinase gene: known as BRAF, where the normal Valine (V) amino acid at position 600 is replaced by Glutamic Acid (E), causing it to be constantly "on" and driving cancer growth, especially in melanoma, thyroid, and colorectal is a crucial oncogenic driver in cancers like melanoma, lung, and colorectal cancers. BRAF/MEK inhibitors” are targeted cancer drugs that block the MAP kinase (Mitogen-Activated Protein kinase)  pathway, with common FDA-approved combinations including Dabrafenib + Trametinib, Vemurafenib + Cobimetinib, and Encorafenib + Binimetinib, used primarily for melanomas and other cancers with a BRAF V600 mutation, significantly improving outcomes compared to single-agent therapy, making it a prime target for specific drugs called BRAF/MEK inhibitors (e.g., vemurafenib, dabrafenib, trametinib) that block the hyperactive MAPK pathway, significantly improving patient outcomes, though resistance development remains a challenge [7-9].
• KRAS: Mutations like G12C (G12C refers to the KRAS G12C mutation, a specific genetic change (Glycine to Cysteine at amino acid position 12) in the KRAS gene, a powerful cancer driver, especially in non-small cell lung cancer (NSCLC) and colorectal cancer, targeted by drugs like Sotorasib (Lumakras/Lumykras) and Adagrasib, which block this mutated protein to stop cancer growth ) are increasingly targetable with specific inhibitors, often seen in smokers.
• MET (Mesenchymal-Epithelial Transition or Hepatocyte Growth Factor Receptor) a receptor tyrosine kinase involved in cell growth; Exon 14 skipping mutations or gene amplification can occur, addressed with MET inhibitors.
• RET stands for Rearranged during Transfection, another receptor tyrosine kinase important for nerve, kidney, and thyroid development, often mutated in cancers like thyroid and lung cancer: Gene fusions or mutations treated with RET inhibitors, common in non-smokers.
• HER2 (ERBB2) Human Epidermal growth factor Receptor 2, also known as Receptor tyrosine kinase erbB-2, a protein crucial for normal cell growth, but its overexpression drives many cancers like breast and gastric cancers. It's part of the EGF receptor family, often called HER2/neu, and acts as a key biomarker for targeted therapies. : Mutations or amplification can be targeted.
• NTRK: Gene fusions across several NTRK genes, responsive to NTRK inhibitors. NTRK stands for Neurotrophic Tyrosine Receptor Kinase, a family of genes (NTRK1, NTRK2, NTRK3) that code for TRK receptors** (TrkA, TrkB, TrkC), crucial for nerve development but which, when fused with other genes in cancer, create oncogenic drivers targeted by specific inhibitors like larotrectinib and entrectinib

• TRK receptors** stand for Tropomyosin Receptor Kinases, a family of three receptor tyrosine kinases (TrkA, TrkB, TrkC) crucial for neuronal survival, differentiation, and growth, activated by neurotrophins like NGF, BDNF, and NT-3. They are encoded by the NTRK genes and play vital roles in the nervous system, with dysregulation linked to neurodegenerative diseases and cancer [7-9].

Other Important Biomarkers are:

• PD-L1 (Programmed Death-Ligand 1): Expression levels guide eligibility for immunotherapy (checkpoint inhibitors).
• TP53 (Tumor Protein p53): a crucial tumor suppressor gene (often called "the guardian of the genome") that prevents cancer by regulating cell cycles, and is frequently mutated in human cancers, also known by names like cellular tumor antigen p53. Very common mutation, but lacks direct targeted therapy, though relevant for prognosis/resistance. 

Testing Methods

• NGS (Next-Generation Sequencing): Comprehensive profiling of multiple genes simultaneously.
• IHC (Immunohistochemistry) & FISH: Used for detecting specific protein expression (PD-L1) or gene rearrangements (ALK, ROS1).
• Liquid Biopsy: Detects circulating tumor DNA (ct-DNA) in blood for less invasive testing or monitoring resistance [7-9].

Rational Combinations and Therapeutic Synergy

Combination strategies have become an essential feature of modern lung cancer therapy.

Chemo-immunotherapy, now a frontline standard for many patients with advanced NSCLC, improves progression-free and overall survival by enhancing tumor antigen release and immune priming [6].

Radiation therapy combined with immunotherapy (iRT) is also gaining traction. Radiotherapy can increase neoantigen exposure and modulate the tumor microenvironment, contributing to the rare but striking abscopal effect [7]. Ongoing trials are refining optimal sequencing, dose fractionation, and patient selection biomarkers.

Immunotherapy with targeted therapy—including EGFR, ALK, and KRAS inhibitors—remains promising but challenging, as toxicities such as pneumonitis require carefully designed regimens [8].

Cellular Immunotherapies: Moving Beyond Checkpoint Blockade

Next-generation cellular therapies represent an exciting frontier.

CAR-T cell therapy, transformative in hematologic malignancies, is being adapted for lung cancer through targets such as EGFR, MSLN, and MUC1 [9]. Innovations such as “armored” CAR-T cells and dual-antigen recognition constructs aim to overcome the immunosuppressive solid tumor microenvironment.

Tumor-infiltrating lymphocyte (TIL) therapy, enabled by advances in T-cell expansion, has shown activity in metastatic NSCLC, particularly in tumors with high mutational burden [10].

Natural killer (NK) cell–based therapies, including allogeneic and engineered variants, offer off-the-shelf immunotherapeutic potential with reduced risk of graft-versus-host disease [11].

Cancer Vaccines and Neoantigen-Based Approaches

Cancer vaccines have re-emerged as powerful adjuncts to ICIs.

Personalized neoantigen vaccines, guided by tumor genomic sequencing, can elicit robust cytotoxic T-cell responses and have demonstrated early evidence of clinical benefit in lung cancer [12].

mRNA vaccine platforms, validated during the COVID-19 pandemic, enable rapid production of individualized tumor vaccines with high immunogenicity and favorable safety profiles [13].

Oncolytic Viral Immunotherapy and Tumor Microenvironment Modulation

Oncolytic viruses (OVs) are engineered to selectively infect and lyse tumor cells while activating systemic antitumor immunity. Agents such as T-VEC and next-generation OVs expressing cytokines or immune agonists are under investigation for lung cancer [14-19].

Simultaneously, therapeutic strategies targeting the tumor microenvironment (TME)—including TAMs, MDSCs, TGF-β, and adenosine pathways—aim to dismantle barriers to effective immune infiltration and activation [15]. Nanoparticle-based platforms and bioengineered delivery systems are enabling precise intratumoral delivery of immunomodulatory agents [16-19].

Artificial Intelligence and Precision Immuno-Oncology

Artificial intelligence (AI) is accelerating biomarker discovery and treatment stratification. Radiomic and pathomic signatures can noninvasively predict response to immunotherapy, while machine learning models integrate genomic, transcriptomic, and immunologic datasets to guide individualized treatment [17-19].

These technologies represent a critical step toward adaptive, real-time precision immunotherapy.

Essential Future Directions include:

The next era of immunotherapy in lung cancer will likely involve:

• Bispecific antibodies targeting dual immune pathways
• TCR-engineered T cells with enhanced tumor specificity
• Intranasal or inhaled immunotherapies for localized drug delivery
• Microbiome modulation to enhance systemic immune responses
• Integration of liquid biopsy monitoring for dynamic therapy adjustment

Conclusion

Although notable challenges remain—including immune-related toxicities, heterogeneous response rates, and cost barriers—the pace of discovery is unprecedented. The convergence of immunology, genomic science, biomedical engineering, and artificial intelligence is redefining what is possible in lung cancer care. Immunotherapy is no longer an adjunct; it is shaping, essential; and  new therapeutic modern ecosystem, where long-term disease control is widespread increasingly achievable. As research accelerates, the field moves closer to a future in which lung cancer outcomes are transformed by the very power of the patient’s own immune system.

  The inhibitory TME (the inhibitory Tumor Microenvironment - TME) encompasses diverse immune system cells, including inhibitory cells and those with antitumor activity. MDSCs (Myeloid-Derived Suppressor Cells),, Tregs  (Regulatory T cells),, and M2 macrophages are notable among the inhibitory and tumor-associated cells. In contrast, antitumor cells such as NK and CD8⁺ cytotoxic T lymphocytes (CTLs) are specifically responsible for targeting and eliminating tumor cells. Conditions such as reduced oxygen concentration and heightened acidity prevail within the TME. Furthermore, tumor cells express inhibitory molecules like PD-1 (Programmed cell death protein 1,) which interact with PD-L1 (Programmed cell death ligand 1), on the surface of CTLs Cytotoxic T Lymphocytes (or Cytotoxic T-cells), diminishing the antitumor activity of these cells, which is the base of ICI therapy (Immune Checkpoint Inhibitor therapy). However, it is noteworthy that monotherapy and conventional therapies such as surgery, chemotherapy, targeted therapies, radiotherapy, or immunotherapeutic methods exhibit limited effectiveness. Based on the available evidence, a more favorable strategy is combination therapy [20].

*CAR-T cells is Chimeric Antigen Receptor T-cells, a type of gene therapy where a patient's own T-cells (a white blood cell) are genetically modified to express synthetic receptors (CAR) that recognize and attack specific cancer cells, making them powerful tools in treating some cancers.

**MDSCs (Myeloid-Derived Suppressor Cells), Tregs (Regulatory T cells), and M2 macrophages are key immunosuppressive players, often found together in the tumor microenvironment and inflamed tissues, working collaboratively through direct contact and secreted factors (like IL-10, TGF-β) to dampen anti-tumor immunity by suppressing T cells and promoting tumor growth, angiogenesis, and metastasis, with MDSCs actively inducing Tregs and shaping M2 macrophage polarization to create a tolerogenic environment, forming a powerful network for immune evasion.

References

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1. Capella, M. P., et al. A Review of Immunotherapy in Non-Small-Cell Lung Cancer. PMC / open review (2024) — recent, clinically focused review summarizing ICI landscape and combinations. PMC
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1. https://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq, accessed Tuesday, 12/09/2025 at 20.00 p.m.
2. Adrian Hunis, Melisa Hunis, Journal of Lung, Pulmonary & Respiratory Research, eISSN: 2376-0060 , J Lung Pulm Respir Res. 2025;12(1):13-16. DOI: 15406/jlprr.2025.12.00325
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1. Heeke, S., et al. Tumor mutational burden assessment as a predictive biomarker. PMC review (2018). PMC
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1. Wang, V., et al. Systematic review of CAR-T cell clinical trials (up to 2022). PMC (2023) — landscape summary and barriers for solid tumours. PMC

1. Trudu, L., et al. CAR-T for Lung Cancers: Challenges and Innovations. Review (2025) — recent analysis of innovations addressing the unique obstacles in lung cancer. ScienceDirect

1. Zhou, C., et al. Amivantamab plus chemotherapy in EGFR exon 20 NSCLC. NEJM (2023) — example of bispecific/targeted antibody in lung cancer. New England Journal of Medicine+1
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1. Reuters/industry coverage: Merck discontinues anti-TIGIT + pembrolizumab lung cancer trial after negative interim (news report covering 2024 halt of vibostolimab combinations) — relevant when discussing translational challenges and failed targets. Reuters
2. “News & coverage of recent randomized CAR-T solid tumour trial successes (2024–2025 coverage; early but notable)”. Example: press reporting on trials showing CAR-T benefit in gastric/GEJ solid tumours (2025). Use with caution; cite as emerging evidence rather than established lung-cancer standard. The Guardian+1
3. Yuanlin Wu, Guangmao Yu, Ketao Jin, Jun Qian, Advancing non-small cell lung cancer treatment: the power of combination immunotherapies, Front. Immunol., 02 July 2024, Sec. Cancer Immunity and Immunotherapy Volume 152024 https://doi.org/10.3389/fimmu.2024.1349502