A pan-cancer systematic review identifies circulating protein signatures that predict outcomes to immune checkpoint inhibitors before therapy begins. Across 49 pre-treatment cohorts, the analysis reports candidate biomarkers spanning inflammation markers and T-cell activation ligands, creating a framework for which patients may benefit more from checkpoint blockade and where prognostic noise could be reduced. The study’s emphasis on pre-treatment proteins aligns with the industry push toward faster, noninvasive stratification—particularly where tissue-based assays are slow, limited, or infeasible. By aggregating across cancer types, the work also highlights which signals appear transferable versus context-specific. For clinical development, the implication is direct: these signatures can be used to enrich trials, interpret heterogeneity, and potentially guide companion diagnostics design tied to immunotherapy response rather than broad risk categories.