Biomedicines. 2025 Jul 14;13(7):1717. doi: 10.3390/biomedicines13071717.

ABSTRACT

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet severe immune-related adverse events (irAEs) often necessitate immunotherapy discontinuation and cause life-threatening complications. Circulating plasma proteins, dynamically accessible and functionally linked to immunity, may predict and offer novel targets for irAEs. Methods: Leveraging multi-omics integration, we conducted bidirectional two-sample Mendelian randomization (MR) using protein quantitative trait loci (pQTLs) from 4998 plasma proteins and genome-wide association data of irAE phenotypes. A causal inference framework combining colocalization analysis, multivariable MR (MVMR) adjusting for body mass index (BMI) confounding, and mediation MR elucidated BMI-independent pathways. Systems biology approaches including tissue-specific expression profiling, pathway enrichment, and protein interaction network analysis revealed spatial and functional drivers of irAE pathogenesis. Results: Proteome-wide MR mapping identified eight plasma proteins (CCL20, CSF1, CXCL9, CD40, TGFβ1, CLSTN2, TNFSF12, TGFα) causally associated with all-grade irAEs, and five (CCL20, CCL25, CXCL10, ADA, TGFα) with high-grade irAEs. Colocalization prioritized CD40/TNFSF12 (all-grade) and ADA/CCL25 (high-grade) as therapeutic targets (PPH4 > 0.7). CXCL9/TNFSF12 (all-grade) and CCL25 (high-grade) exerted BMI-independent effects, suggesting intrinsic immune dysregulation mechanisms. Tissue-specific gene expression patterns, CSF1, TGFβ1 in lung, TNFSF12 in the ileum may explain organ-specific irAE vulnerabilities. High-grade irAEs correlated with compartmentalized immune dysregulation and IL-17/immunodeficiency pathway activation. Conclusions: This study establishes the causal atlas of plasma proteins in irAE pathogenesis, bridging biomarker discovery with actionable therapeutic targets. These advances align with next-generation immunotherapy goals: maximizing efficacy while taming the immune storm.

PMID:40722787 | PMC:PMC12293052 | DOI:10.3390/biomedicines13071717

World J Clin Cases. 2025 Jul 26;13(21):105066. doi: 10.12998/wjcc.v13.i21.105066.

ABSTRACT

BACKGROUND: Circulating tumor DNA (ctDNA)-based liquid biopsy has been found to be effective for the detection of minimal residual disease and the evaluation of prognostic risk in various solid tumors, with good sensitivity and specificity for identifying patients at high risk of recurrence. However, use of its results as a biomarker for guiding the treatment and predicting the prognosis of nasopharyngeal carcinoma (NPC) has not been reported.

CASE SUMMARY: In this case study of a patient with stage IVb NPC, we utilized ctDNA as an independent biomarker to guide treatment. Chemotherapy was administered in the early stages of the disease, and local intensity-modulated radiation therapy was added when the patient tested positive for ctDNA, while radiation therapy was stopped and the patient was observed when the ctDNA test was negative. During the follow-up period, ctDNA signals became positive before tumor progression and became negative again at the end of treatment. We also explored the potential of ctDNA in combination with Epstein-Barr virus (EBV) DNA status to predict the prognosis of NPC patients, as well as the criteria for selecting genetic mutations and the testing cycle for ctDNA analysis.

CONCLUSION: The results of ctDNA-based liquid biopsy can serve as an independent biomarker, either independently or in conjunction with EBV DNA status, to guide the treatment and predict the prognosis of NPC.

PMID:40726932 | PMC:PMC12068179 | DOI:10.12998/wjcc.v13.i21.105066