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Review
. 2025 Jul 17:15:1625212.
doi: 10.3389/fonc.2025.1625212. eCollection 2025.

The prognostic and predictive value of peripheral immune-related proteins in patients with lung cancer treated with radiotherapy

Shaowen Lyu  1 , Rianne D W Vaes  1 , Iris E W G Laven  1 , Francesco Cortiula  1   2 , Lizza E L Hendriks  3 , Marc A Vooijs  1 , Dirk K M De Ruysscher  1
Affiliations
Review

The prognostic and predictive value of peripheral immune-related proteins in patients with lung cancer treated with radiotherapy

Shaowen Lyu et al. Front Oncol. .

Abstract

Lung cancer is the leading cause of cancer-related death world-wide. Although the standard of care for patients with advanced stage lung cancer has significantly improved with the advent of immunotherapy and targeted agents, the overall prognosis remains poor. It highlights the need for improved patient selection utilizing prognostic and predictive biomarkers. Given the limited feasibility of serial lung tumor tissue biopsies, liquid biopsies have gained specific interest in achieving this aim. Radiotherapy, commonly used alongside systemic treatments, can induce the release of immuno-stimulatory and immuno-suppressive molecules, triggering the immune- and inflammatory responses and releasing associated molecules. This review specifically focusses on immune-related molecules that are measurable in the blood and which have potential prognostic and/or predictive value in patients with lung cancer treated with radiotherapy alone or in combination with systemic agents. Such immune-related molecules include cytokines and chemokines, damage-associated molecular patterns, soluble receptors and ligands, and proteins expressed on the immune cell surface of circulating immune cells. Classical cytokines IL-6, IL-8, and TGF-β1 were the most studied molecules in patients with lung cancer treated with radiotherapy and were associated with poor survival and increased risk of radiation-induced toxicity. To date, there are still some barriers before these promising findings can be implemented in regular clinical practice. Practical points to achieve this goal are also addressed in this review.

Keywords: biomarkers; immune-related proteins; lung cancer; peripheral blood; predictive; prognostic; radiotherapy.

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Conflict of interest statement

FC reports outside of this manuscript personal fees as invited speaker from AstraZeneca, Roche, and Johnson & Johnson and as advisor to Regeneron and MSD; institutional funding as a local principal investigator PI from AstraZeneca and MSD; reports non-financial interests as member of the ESMO guideline committee on metastatic NSCLC. LH reports outside of this manuscript fees as an invited speaker from AstraZeneca, Bayer, Lilly, MSD, high5oncology, Takeda, Janssen, GSK, Sanofi, Pfizer, Medtalks, Benecke, VJOncology, Medimix; all payments were paid to the institution with the exception of Medtalks, Benecke, VJOncology, Medimix; fees paid to her institution for advisory board membership from Advisory boards: Abbvie, Amgen, Anhearth, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi, GSK, Janssen, Lilly, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Summit Therapeutics, and Takeda; institutional research grants from Roche Genentech, AstraZeneca, Boehringer Ingelheim, Takeda, Merck, Pfizer, Novartis, and Gilead; institutional funding as a local principal investigator PI from AstraZeneca, GSK, Novartis, Merck, Roche, Takeda, Blueprint, Mirati, Abbvie, Gilead, MSD, Merck, Amgen, Boehringer Ingelheim, Pfizer, Daiichi, Amgen, and BMS. Member guideline committees: Dutch guidelines on NSCLC, brain metastases and leptomeningeal metastases, ESMO guidelines on metastatic NSCLC, non-metastatic NSCLC, and SCLC non-financial. Other non-financial: former secretary and current chair NVALT studies foundation, subchair of EORTC metastatic NSCLC systemic therapy, and vicechair scientific committee Dutch Thoracic Group. DR reports outside of this manuscript research grants from and support and advisor to: AstraZeneca, BMS, Beigene, Philips, and Olink institutional financial interests, no personal financial interests; Advisory board: Eli-Lily institutional financial interests, no personal financial interests. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Prognostic and predictive biomarkers of peripheral immune-related proteins in patients with lung cancer treated with (chemo) radiotherapy. (C)RT, (chemo) radiotherapy; OS, overall survival; PFS, progression-free survival); RILI, radiation-induced lung injury. Created with BioRender.com.
Figure 2
Figure 2
Current challenges and limitations to implement promising biomarkers in daily clinical care. 1) Bias is the main cause of failure in biomarker discovery and validation studies and can occur during patient selection, specimen collection, specimen analysis, and patient evaluation; 2) New technological advances have significantly enhanced the capacity for biomarker discovery, however, these innovations are expensive hampering the implementation thereof in large-scale studies; 3) Assays from different manufacturers vary in sensitivity and specificity. As a consequence, results from different trials cannot be compared. 4) Most assays are designated for research use only (RUO) and are not validated for diagnostic applications. 5) Manufacturers have to make strong investments (time, resources, and budget) to meet the new regulatory requirements to bring an in vitro diagnostic medical device (IVD) on the market (IVDR); 6) Lack of multidisciplinary collaboration among researchers, clinicians and industrial partners. Created with BioRender.com.
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