Innate immune axis in non–muscle-invasive bladder cancer: Neutrophils, macrophages, natural killer cells, and dendritic cells in prognosis and BCG response

Abstract

Background: Non–muscle-invasive bladder cancer (NMIBC) accounts for most newly diagnosed urothelial carcinomas and is characterized by frequent recurrences and a significant risk of progression despite transurethral resection and Bacillus Calmette–Guérin (BCG) therapy. Conventional risk models based on stage, grade, tumor size, multiplicity, and carcinoma in situ explain only part of the heterogeneity of clinical outcomes. Innate immune cells are directly engaged by intravesical therapy and influence downstream T- and B-cell responses, but have been less comprehensively reviewed than adaptive lymphocytes. Objective: To evaluate prognostic and therapeutic roles of innate immune cells in NMIBC and their impact on BCG response. This review summarizes current data on neutrophils, tumor-associated macrophages (TAMs), natural killer (NK) cells, and dendritic cells (DCs) in NMIBC. Quantitative and spatial studies show that tumor-infiltrating neutrophils and M2-skewed TAMs accumulate in high-grade and pT1 tumors, are associated with diffuse carcinoma in situ and adverse histological features, and correlate with higher risks of recurrence, progression, and BCG failure. In contrast, preserved NK-cell infiltration and function, together with mature, co-stimulatory DC phenotypes, appear to support effective cytotoxic responses and sustained immune surveillance. Systemic indices such as the pre-operative and pre-BCG neutrophil-to-lymphocyte ratio, tissue-based measures of tumor-infiltrating neutrophils, cluster of differentiation (CD)68+ and CD163+ TAM burden and phenotype, and integrated effector-to-suppressor scores linking CD8+ T cells, TAMs, and regulatory T cells consistently associate with prognosis and BCG response in multiple cohorts. These markers are biologically plausible and inexpensive, but require prospective validation and standardization before routine clinical use. Conclusion: Preclinical and early clinical work on macrophage-directed agents, intravesical nano-immunotherapies, DC-based strategies, and NK-directed approaches suggests that modulation of innate immunity may complement BCG and checkpoint inhibition in high-risk and BCG-unresponsive NMIBC.