Bladder cancer (BC) is one of the most common malignancies of the genitourinary system, ranking fourth in incidence among cancers diagnosed in men worldwide [1]. The age-standardized incidence rate (per 100,000 people/year) is 9.5 for men and 2.4 for women [2]. Muscle-invasive bladder cancer (MIBC) accounts for 30 % of all bladder cancers and is characterized by rapid progression, frequent recurrence, and poor prognosis [3]. The high heterogeneity and complex tumor microenvironment (TME) of BC pose major challenges for its treatment. The TME, composed of tumor cells, immune cells, stromal components, and others, dynamically interacts, profoundly influencing tumor immune evasion, metastasis, and therapy resistance [4]. Although neoadjuvant chemotherapy combined with radical cystectomy is the standard treatment for MIBC, the survival benefit of chemotherapy is limited and its side effects are significant [5,6]. With growing understanding of tumor-immune interactions, immune checkpoint inhibitors (ICIs) and other immunotherapies have brought new hope for BC treatment.

The establishment of molecular subtypes has significantly improved the diagnosis, treatment, and prognosis prediction of BC. These subtypes are based on clinical characteristics or gene expression profiles, including miRNA, LncRNA, or other specific protein-coding genes [[7], [8], [9], [10], [11]]. However, existing prognostic biomarkers still fall short in predicting individualized responses to immunotherapy, highlighting the urgent need for novel indicators that can more accurately reflect the immune status within the TME.

Natural killer (NK) cells, as central components of the innate immune system, play a unique role in anti-tumor immunity due to their ability to mediate non-specific killing independent of prior sensitization and major histocompatibility complex (MHC) restriction [12,13]. Unlike other adaptive immune cells, NK cells can rapidly recognize and eliminate malignantly transformed cells. This characteristic makes them a crucial bridge connecting innate and adaptive immunity and reveals significant potential in immunotherapy [13]. With advances in NK cell culture and expansion technologies, NK cell adoptive therapy has become an important part of cancer immunotherapy.

The prognostic value of NK cells has been confirmed in various solid tumors [14]. For instance, studies in glioma and rectal cancer have shown that NK cell-related gene signatures or an NK-like response are associated with better patient survival outcomes [15,16]. However, systematic research on prognostic signatures based on NK cell-related genes remains scarce in BC. Given the dual functions of NK cells in direct tumor killing and immune microenvironment modulation, we hypothesize that constructing an NK cell-related gene signature could provide a more robust tool for predicting prognosis and response to immunotherapy in BC, potentially surpassing existing indicators.

This study aims to construct and validate a prognostic signature based on NK cell-related genes and to investigate its value in predicting the prognosis and immunotherapy response of patients with BC.