Circulating proteomic biomarkers of immune checkpoint inhibitor outcomes: a comprehensive pan-cancer review of pre-treatment cohorts

Immune checkpoint inhibitors (ICIs) have revolutionized cancer management; nevertheless, a large number of patients fail to respond to treatment. Despite extensive research efforts, there is a lack of accurate non-invasive biomarkers for prognosis and treatment outcome prediction. In this systematic review, we aim to record and evaluate studies investigating blood-circulating protein biomarkers and their association with ICIs outcomes. A literature search of PubMed and the Cochrane Library (on December 18, 2025) for studies investigating plasma biomarkers in ICI-treated cohorts at baseline was performed. Results were synthesized across cancer types and proteomic technologies, based on a vote-counting approach. The QUIPS (Quality In Prognosis Studies) tool was used to assess the risk of bias. A total of 49 studies meeting the eligibility criteria were included in the analysis. The majority of these studies focused on lung cancer ( n = 21) and melanoma ( n = 13) and used Olink ( n = 23) and mass spectrometry ( n = 15) platforms. Synthesis of the results revealed that high pre-treatment systemic levels of IL-6, CXCL8, ANGPT2, CRP, CCL3, CSF1, CXCL10, TNFSF14, and SAA1/2 were associated with poorer outcomes in ICI treated patients, while elevated levels of soluble T-cell ligands (ICOSLG, TNFSF10, and FASLG) and CXCL5 were reproducibly correlated with improved treatment outcomes. To conclude, despite limitations linked to the heterogeneity of proteomic platforms and variability in outcome reporting across studies, consistent patterns emerged: markers of systemic inflammation were associated with poor response, while proteins involved in T-cell activation and signaling were linked to better outcomes.