Tumor Immune Infiltration as a Predictor of Response to Neoadjuvant Chemo-Immunotherapy in Muscle-Invasive Bladder Cancer: An Integrative TCGA Analysis

Background: Muscle-invasive bladder cancer (MIBC) is an aggressive disease with heterogeneous responses to neoadjuvant chemotherapy and emerging chemo-immunotherapy combinations. Reliable biomarkers to predict treatment responsiveness before therapy initiation are needed to guide patient selection. Objective: To identify genomic and immune-related features associated with predicted responsiveness to neoadjuvant chemo-immunotherapy in MIBC using The Cancer Genome Atlas bladder cancer cohort (TCGA-BLCA). Methods: A retrospective bioinformatics analysis of TCGA-BLCA data was performed, evaluating gene expression, somatic mutations, tumor mutational burden (TMB), DNA damage response (DDR) gene status, and immune infiltration signatures. Immune enrichment metrics were derived from transcriptomic data. In the absence of direct treatment response data, a surrogate immune response classification was applied. Associations were analyzed using descriptive statistics and Firth’s penalized logistic regression. Results: Likely responders exhibited significantly higher global immune infiltration, including increased ImmuneScore and enrichment of cytotoxic and innate immune cells. In multivariable analysis, ImmuneScore was the only independent predictor of inferred responsiveness (p = 0.003). Conclusion: Global immune infiltration is the strongest determinant of inferred response to neoadjuvant chemo-immunotherapy in MIBC, supporting immune profiling as a key stratification tool.