BackgroundUrothelial bladder cancer is most frequently diagnosed at the non-muscle-invasive stage (NMIBC). However, recurrences and interventions for intermediate and high-risk NMIBC patients impact the quality of life. Biomarkers for patient stratification could help to avoid unnecessary interventions whilst indicating aggressive measures when required.MethodsIn this study, immuno-oncology focused, multiplexed proximity extension assays were utilised to analyse plasma (n= 90) and urine (n= 40) samples from 90 newly-diagnosed and treatment-naïve bladder cancer patients. Public single-cell RNA-sequencing and microarray data from patient tumour tissues and murine OH-BBN-induced urothelial carcinomas were also explored to further corroborate the proteomic findings.ResultsPlasma from muscle-invasive, urothelial bladder cancer patients displayed higher levels of MMP7 (p= 0.028) and CCL23 (p= 0.03) compared to NMIBC patients, whereas urine displayed higher levels of CD27 (p= 0.044) and CD40 (p= 0.04) in the NMIBC group by two-sided Wilcoxon rank-sum tests. Random forest survival and multivariable regression analyses identified increased MMP12 plasma levels as an independent marker (p< 0.001) associated with shorter overall survival (HR = 1.8,p< 0.001, 95% CI:1.3–2.5); this finding was validated in an independent patient OLINK cohort, but could not be established using a transcriptomic microarray dataset. Single-cell transcriptomics analyses indicated tumour-infiltrating macrophages as a putative source of MMP12.ConclusionsThe measurable levels of tumour-localised, immune-cell-derived MMP12 in blood suggest MMP12 as an important biomarker that could complement histopathology-based risk stratification.As MMP12 stems from infiltrating immune cells rather than the tumor cells themselves, analyses performed on tissue biopsy material risk a biased selection of biomarkers produced by the tumour, while ignoring the surrounding microenvironment.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-023-11100-0.