Logo

Precision Reprogramming of Lung Cancer Biomarkers via CRISPR/Cas9: A Paradigm Shift in Personalized Immunotherapy

Authors

  • Mohd Rizwan Jameel

    Centre for Interdisciplinary Research in Basic Science, Jamia Milia Islamia, New Delhi – 110025, India

  • Amar Arora

    Banasthali Vidyapith, Banasthali -304022, Rajasthan, India

  • Prem Shankar Mishra

    Faculty of Pharmacy, Vidya University, Meerut 250002, Uttar Pradesh, India

  • Hina Jameel

    Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh-202001, India

  • Mudassir Jan Makhdoomi

    All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India

  • Abid Ali Sheikh

    National Institute of Biologicals, Sector 62, Noida -201309, Uttar Pradesh, India

DOI:

https://doi.org/10.30683/1927-7229.2025.14.15

Keywords:

CRISPR/Cas9, lung cancer, biomarkers, immunotherapy, precision oncology, PD-L1, ctDNA, antigen presentation, genome editing, T-cell engineering

Abstract

Lung cancer persists as the leading cause of cancer-related mortality globally, largely due to late detection, genomic complexity, and limited durability of existing therapeutic interventions. The integration of CRISPR/Cas9 gene-editing systems with biomarker-driven therapeutic strategies represents a transformative advance in precision oncology. Biomarkers—including genetic mutations, epigenetic alterations, protein signatures, and circulating analytes—enable early detection, patient stratification, and dynamic monitoring of therapeutic response. CRISPR/Cas9 offers a unique opportunity to directly reprogram these biomarkers or the pathways regulating them, enhancing tumor immunogenicity, reversing immune evasion mechanisms, and strengthening anti-tumor immune responses. Preclinical models demonstrate that CRISPR-mediated biomarker editing can restore antigen presentation, augment T-cell cytotoxicity, sensitize resistant tumors to immunotherapy, and improve tumor regression. Early clinical trials further validate the feasibility and safety of CRISPR-engineered immune cells in patients.

However, major challenges persist, including off-target editing, inefficient delivery to solid tumors, tumor microenvironment–mediated suppression, and ethical considerations linked to genome manipulation. Rapid advancements in editing fidelity, lipid nanoparticle systems, viral vectors, engineered vesicles, high-throughput biomarker discovery, and artificial intelligence–assisted CRISPR design are expected to accelerate clinical translation. This review synthesizes the current landscape, mechanistic underpinnings, emerging applications, and future directions of CRISPR/Cas9-enabled biomarker engineering for lung cancer immunotherapy, positioning this technology as a cornerstone of next-generation personalized oncology.

References

[1] Kratzer TB, Bandi P, Freedman ND, Smith RA, Travis WD, Jemal A, Siegel RL. Lung cancer statistics, 2023. Cancer 2024; 130(8): 1330-48.

[2] Leiter A, Veluswamy R, Wisnivesky JP. The global burden of lung cancer: current status and future trends. Nat Rev Clin Oncol 2023; 20(9): 624-39.

[3] Liu B, Saber A, Haisma HJ. CRISPR/Cas9 as a tool for identifying new cancer targets. Drug Discov Today 2019; 24(4): 955-70.

[4] Jameel MR, Ansari Z, Al-Huqail AA, et al. CRISPR editing of soluble starch synthesis enzyme in rice. Agronomy 2022; 12(9): 2206.

[5] Hussein AD, Al-Shammari MJ, Alqaisy MR, et al. Emerging biomarkers in cancer detection and prognosis: A comprehensive review. Int J Immunol 2025; 7(1): 1-12.

[6] Das S, Dey MK, Devireddy RV, et al. Biomarkers in cancer detection, diagnosis, and prognosis. Sensors (Basel) 2023; 24(1): 37.

[7] Chellini E, Colangelo T, Fina E, et al. Biomarkers and lung cancer early detection: state of the art. Cancers (Basel) 2021; 13(15): 3919.

[8] Chabon JJ, Hamilton EG, Kurtz DM, et al. Integrating genomic features for non-invasive early lung cancer detection. Nature 2020; 580(7802): 245-51.

[9] Rodríguez MF, Ajona D, Seijó L, et al. Molecular biomarkers in early-stage lung cancer. Transl Lung Cancer Res 2021; 10(2): 1165-85.

[10] Nelson AC, Meyer M, Katdare R, et al. Early detection of lung cancer via 3D analysis of sputum cells. J Clin Oncol 2014; 32(15 Suppl): 7547.

[11] Saman H, Raza A, Patil K, et al. Non-invasive biomarkers for early lung cancer. Cancers (Basel) 2022; 14(23): 5782.

[12] Yang B, Li X, Ren T, et al. Autoantibodies as diagnostic biomarkers for lung cancer: A systematic review. Cell DEATH Discov 2019; 5(1).

[13] Villalobos P, Wistuba II. Lung cancer biomarkers. Hematol Oncol Clin North Am 2016; 31(1): 13-29.

[14] Velcheti V, Schalper KA, Carvajal D, et al. PD-L1 expression in NSCLC. Lab Invest 2013; 94(1): 107-16.

[15] Sánchez-Herrero E, Serna-Blasco R, Lope LRD, ET AL.ctDNA as a cancer biomarker. Front Oncol 2022; 12.

[16] Zhou X, Lü X, Wu H, et al. Diagnostic performance of SHOX2 promoter methylation for lung cancer identification: A meta-analysis update. Cancer Med 2021; 12(24): 3327-32.

[17] Wei B, Wu F, Xing W, et al. A panel of DNA methylation biomarkers for detection and improving diagnostic efficiency of lung cancer. SCI REP 2021; 11(1).

[18] Chen Z, Guo Y, Da Z, et al. CDKN2A as a biomarker for immune infiltrates in multiple cancers. Front Cell Dev Biol 2021; 9. Accessed 2025 Sep 12.

[19] Liu J, Chen Z, Li Y, et al. PD-1/PD-L1 checkpoint inhibitors in tumor immunotherapy. Front Pharmacol 2021; 12. Accessed 2025 May 17.

[20] Yang K, Halima A, Chan TA. Antigen presentation in cancer—mechanisms and clinical implications for immunotherapy. Nat Rev Clin Oncol 2023; 20(9): 604-23.

[21] Sobhani N, Tardiel-Cyril DR, Davtyan A, et al. CTLA-4 in regulatory T cells for cancer immunotherapy. Cancers (Basel) 2021; 13(6): 1440.

[22] Long L, Zhang X, Chen F, et al. The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy. Genes Cancer 2018; 9(5-6): 176-89.

[23] Hu L, Sun C, Yuan K, et al. Expression, regulation, and function of PD-L1 on non-tumor cells in the tumor microenvironment. Drug Discov Today 2024; 104181.

[24] Babamohamadi M, Mohammadi NK, Faryadi E, et al. Anti-CTLA-4 nanobody as a promising approach in cancer immunotherapy. Cell Death Dis 2024; 15(1).

[25] Shi L, Meng T, Zhao Z, et al. CRISPR knockout of CTLA-4 enhances anti-tumor activity of cytotoxic T lymphocytes. Gene 2017; 636: 36-41.

[26] Lei P, Ju Y, Peng F, et al. Applications and advancements of CRISPR-Cas in lung cancer treatment. Front Cell Dev BIOL 2023; 11: 1295084.

[27] Molla KA, Yang Y. CRISPR/Cas-mediated base editing: technical considerations and practical applications. Trends Biotechnol 2019; 37(10): 1121-42.

[28] Chen PJ, Liu DR. Prime editing for precise and highly versatile genome manipulation. Nat Rev Genet 2022; 24(3): 161-77.

[29] Stefanoudakis D, Kathuria-Prakash N, Sun AW, et al. The potential revolution of cancer treatment with CRISPR technology. Cancers (Basel) 2023; 15(6): 1813.

[30] Cheung AH, Chow C, Zhang J, et al. Specific targeting of point mutations in EGFR L858R-positive lung cancer by CRISPR/Cas9. Lab Invest 2018; 98(7): 968-76.

[31] Hazafa A, Mumtaz M, Farooq M, et al. CRISPR/Cas9: A powerful genome editing technique for the treatment of cancer cells with present challenges and future directions. Life Sci 2020; 263: 118525.

[32] Sun D. Design of time-delayed safety switches for CRISPR gene therapy. Sci Rep 2021; 11(1).

[33] Chehelgerdi M, Chehelgerdi M, Khorramian-Ghahfarokhi M, et al. Comprehensive review of CRISPR-based gene editing: mechanisms, challenges, and applications in cancer therapy. Mol Cancer 2024; 23(1).

[34] Han H, Pang JKS, Soh B. Mitigating off-target effects in CRISPR/Cas9-mediated in vivo gene editing. J Mol Med (Berl) 2020; 98(5): 615-32.

[35] Yin H, Kauffman K, Anderson DG. Delivery technologies for genome editing. Nat Rev Drug Discov 2017; 16(6): 387-99.

[36] Tao J, Bauer DE, Chiarle R. Assessing and advancing the safety of CRISPR-Cas tools: from DNA to RNA editing. Nat Commun 2023; 14(1).

[37] National Academies of Sciences, Engineering, and Medicine. Human genome editing: science, ethics, and governance. Washington (DC): National Academies Press; 2017.

[38] Ormond KE, Mortlock DP, Scholes DT, et al. Human germline genome editing. Am J Hum Genet 2017; 101(2): 167-76.

[39] Ewaisha R, Anderson KS. Immunogenicity of CRISPR therapeutics—Critical considerations for clinical translation. Front Bioengbiotechnol 2023; 11.

[40] Tang N, Ning Q, Xu J, et al. Tumor microenvironment-based stimuli-responsive CRISPR/Cas delivery systems: A viable platform for interventional approaches. Colloids Surf B Biointerfaces 2021; 210: 112257.

[41] Yuan M, Huang L, Chen J, et al. The emerging treatment landscape of targeted therapy in non-small-cell lung cancer. Signal Transduct Target Ther 2019; 4(1).

[42] Mino-Kenudson M, Schalper KA, Cooper WA, et al. Predictive biomarkers for immunotherapy in lung cancer: perspective from the IASLC Pathology Committee. J Thorac Oncol 2022; 17(12): 1335-54.

[43] Zhou C, Jing Z, Liu W, et al. Prognosis of recurrence after complete resection in early-stage lung adenocarcinoma based on molecular alterations: a systematic review and meta-analysis. Sci Rep 2023; 13(1).

[44] Wang F, Wang S, Zhou Q. Resistance mechanisms of lung cancer immunotherapy. Front Oncol 2020; 10.

[45] Freitas KA, Belk JA, Sotillo E, et al. Enhanced T cell effector activity by targeting the Mediator kinase module. Science 2022; 378(6620)

[46] Rahman S, Ikram A, Azeem F, et al. Precision genome editing with CRISPR-Cas9. In: Methods Mol Biol 2024: 355-72.

[47] Long KJ, Pitcher TJ, Kurman JS, et al. Using a blood biomarker to distinguish benign from malignant pulmonary nodules. Chest 2023; 164(6): 1572-5.

[48] Xu-Welliver M, Carbone DP. Blood-based biomarkers in lung cancer: prognosis and treatment decisions. TRANSL LUNG Cancer Res 2017; 6(6): 708-12.

[49] Yip BH. Recent advances in CRISPR/Cas9 delivery strategies. Biomolecules 2020; 10(6): 839.

[50] Lu Y, Godbout K, Lamothe G, Tremblay JP. CRISPR-Cas9 delivery strategies with engineered extracellular vesicles. Mol Ther Nucleic Acids 2023; 34: 102040.

[51] Zhang Y, Liang S, Yang H, et al. CRISPR-mediated kinome editing prioritizes a synergistic combination therapy for FGFR1-amplified lung cancer. Cancer Res 2021; 81(11): 3121-33.

[52] Brokowski C, Adli M. CRISPR ethics: moral considerations for applications of a powerful tool. J Mol Biol 2018; 431(1): 88-101.

[53] Zakari S, Niels NK, Olagunju GV, et al. Emerging biomarkers for non-invasive diagnosis and treatment of cancer: a systematic review. Front Oncol 2024; 14.

[54] Dakal TC, Dhakar R, Beura A, et al. Emerging methods and techniques for cancer biomarker discovery. Pathol Res Pract 2024; 155567.

[55] Dara M, Dianatpour M, Azarpira N, Omidifar N. Convergence of CRISPR and artificial intelligence: A paradigm shift in biotechnology. Hum Genet 2024; 41: 201297.

[56] Dixit S, Kumar A, Srinivasan K, et al. Advancing genome editing with artificial intelligence: opportunities, challenges, and future directions. Front Bioengbiotechnol 2024; 11: 1335901. Accessed 2025 Oct 6.

[57] Bhat AA, Nisar S, Mukherjee S, et al. Integration of CRISPR/Cas9 with artificial intelligence for improved cancer therapeutics. J Transl Med 2022; 20(1): 534. Accessed 2025 Jun 17.

[58] Garg P, Singhal G, Pareek S, et al. Unveiling the potential of gene editing techniques in revolutionizing cancer treatment: a comprehensive overview. BBA Rev Cancer 2025; 1880(1): 189233. Accessed 2025 Oct 2.

Downloads

Published

2025-12-30

Issue

Vol. 14 (2025)

Section

Articles

License

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

How to Cite

Precision Reprogramming of Lung Cancer Biomarkers via CRISPR/Cas9: A Paradigm Shift in Personalized Immunotherapy. (2025). Journal of Analytical Oncology, 14, 96-105. https://doi.org/10.30683/1927-7229.2025.14.15

Similar Articles

1-10 of 217

You may also start an advanced similarity search for this article.