Immune-Related Biomarkers in Cancer: Development, Validation, and Challenges in Clinical Practice—A Systematic Review

doi:10.70996/cip.00002

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Cancer Immuno Perspectives ›› 2025, Vol. 1 ›› Issue (1) : 12-19. DOI: 10.70996/cip.00002

Immune-Related Biomarkers in Cancer: Development, Validation, and Challenges in Clinical Practice—A Systematic Review

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Abstract

Cancer immunotherapy, particularly immune checkpoint inhibitors (ICIs), has fundamentally transformed oncology treatment

over the past decade, markedly improving survival across multiple tumor types. However, response rates remain limited, with

only 15-30% of patients deriving clinical benefit, highlighting the critical need for reliable predictive biomarkers. This

systematic review comprehensively examines the current landscape of immune-related biomarkers in cancer, focusing on their

development, validation methodologies, and challenges in clinical translation. We analyze biomarker categories including

tumor microenvironment-based markers (PD-L1, TMB), peripheral blood markers (autoantibodies, inflammatory indices), and

emerging multi-omics approaches. The review further explores the complex validation pathway for clinical implementation,

addressing persistent obstacles such as tumor heterogeneity, technical standardization, and biological complexity. Finally, we

discuss innovative strategies and future directions aimed at enhancing biomarker performance through multi-omics integration,

artificial intelligence, and novel trial designs. The continued evolution of biomarker development holds significant promise for

advancing precision immuno-oncology and optimizing patient outcomes

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Yu Liu, Liang Li.

Immune-Related Biomarkers in Cancer: Development, Validation, and Challenges in Clinical Practice—A Systematic Review

[J]. Cancer Immuno Perspectives. 2025, 1(1): 12-19 https://doi.org/10.70996/cip.00002

References

[1] Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med.

2012;366(26):2443-2454.

[2] Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264.

[3] Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med.

2018;378(2):158-168.

[4] Kim J, Chen H, Mellman I. Cancer immunotherapy: raising the bar. Cell. 2018;174(6):1381-1395.

[5] Whiting PF, Rutjes AW, Westwood ME, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med.

2011;155(8):529-536.

[6] Shea BJ, Reeves BC, Wells GA, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised

studies of healthcare interventions, or both. BMJ. 2017;358:j4008.

[7] Oxford Centre for Evidence-Based Medicine. OCEBM Levels of Evidence. 2011. Available at: https://www.cebm.net/ocebm-levels-of-evidence/.

[8] Tirosh I, Izar B, Prakadan SM, et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science.

2016;352(6282):189-196.

[9] Zilionis R, Engblom C, Pfirschke C, et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations

across species and tissues. Immunity. 2019;50(1):131-146.e10.

[10] Stahl P, Salmén F, Vickovic S, et al. Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science.

2016;353(6294):78-82.

[11] Campbell JD, Yau C. Computational analysis of cancer genomes and transcriptomes. Nat Rev Genet. 2017;18(10):607-620.

[12] Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med.

2012;366(26):2455-2465.

[13] Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520.

[14] Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer

(KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-1550.

[15] Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.

Genome Med. 2017;9(1):34.

[16] Rubio-Camarillo E, Chen J, Chen S, et al. Humanized mice for preclinical evaluation of cancer immunotherapies. Nat Rev Clin Oncol.

2020;17(12):745-763.

[17] Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1-10.

[18] Gettinger SN, Horn L, Jackman DM, et al. Assay comparison of four PD-L1 immunohistochemistry assays in non-small-cell lung cancer. J Clin

Oncol. 2017;35(17):1934-1941.

[19] Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018-2028.

[20] Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med.

2018;378(21):2078-2092.

[21] Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med.

2019;381(21):2020-2031.

[22] Le DT, Durham JN, Smith KN, et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science.

2017;357(6349):409-413.

[23] FDA. Companion and Complementary Diagnostics. 2024. Available at:

https://www.fda.gov/medical-devices/in-vitro-diagnostics/companion-and-complementary-diagnostics.

[24] Detterbeck FC, Boffa DJ, Tan AC, et al. Real-world effectiveness of pembrolizumab in PD-L1-positive non-small-cell lung cancer. J Thorac

Oncol. 2020;15(3):443-452.

[25] Taube JM, Anders RA, Young G, et al. PD-L1 expression in non-small cell lung cancer: a comparison of four immunohistochemical assays. Mod

Pathol. 2016;29(7):820-828.

[26] Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat

Genet. 2019;51(2):202-206.

[27] Yates LA, Campbell IG, Tavaré S, et al. Intratumor heterogeneity: evolution through space and time. Cancer Res. 2015;75(10):1965-1972.

[28] Newman AM, Bratman SV, To M, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med.

2014;20(5):548-554.

[29] Forde PM, Smith KN, Brahmer JR, et al. Discordance of PD-L1 expression between primary and metastatic sites in patients with non-small cell

lung cancer. J Thorac Oncol. 2018;13(1):106-112.

[30] Schalper KA, Tawbi HA, Anagnostou V, et al. Tumor mutational burden and immune checkpoint inhibitor efficacy: a meta-analysis. JAMA Oncol.

2021;7(4):558-568.

[31] Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer

trial in node-positive breast cancer comparing docetaxel-containing versus non-docetaxel-containing adjuvant chemotherapy regimens (the EORTC

10085/BO16348 trial). Ann Oncol. 2013;24(4):1059-1066.

[32] Siu LL, Awad MM, Meric-Bernstam F, et al. Biomarker-directed therapy for advanced solid tumours: American Society of Clinical Oncology

provisional clinical opinion update 2020. J Clin Oncol. 2021;39(2):210-226.

[33] Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J

Med. 2016;375(19):1823-1833.

[34] Howard DS, McGuire V, Hammitt JK, et al. Cost-effectiveness of immune checkpoint inhibitors for advanced non-small-cell lung cancer in the

United States. J Clin Oncol. 2018;36(28):2874-2881.

[35] Patel SP, Kurzrock R. Clinical implications of genomic landscape in cancer immunotherapy. Cancer Cell. 2015;27(5):677-690.

[36] FDA. PD-L1 IHC Assay Comparison Project. 2023. Available at: https://www.fda.gov/media/166582/download.

[37] Thakur BK, Zhang H, Li Z, et al. Exosomes: composition, biogenesis and function. Cell Res. 2014;24(1):22-34.[38] Wang Y, Zhang Y, Li J, et al. Point-of-care testing for cancer biomarkers: recent advances and future trends. Biosens Bioelectron.

2020;165:112394.

[39] Akbay EA, Lo RS, Herter-Sprie GS, et al. STK11/LKB1 deficiency promotes immune evasion and resistance to PD-1 blockade in KRAS-mutant

lung cancer. Cancer Discov. 2019;9(5):610-625.

[40] Huang M, Zhang Y, Chen K, et al. Deep learning-based multi-modal integration predicts immunotherapy response in non-small cell lung cancer.

Comput Biol Chem. 2023;102:107645.

[41] Baas P, Chaft JE, Getnet D, et al. Tepotinib plus gefitinib in EGFR-mutant non-small-cell lung cancer with MET amplification. N Engl J Med.

2021;384(13):1209-1221.

[42] Zaretsky JM, Garcia-Diaz A, Shin DM, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med.

2016;375(8):819-829.