Upper tract urothelial carcinoma (UTUC) is a relatively uncommon malignancy, accounting for 5–10% of all UCs worldwide (1). Notably, its incidence is disproportionately higher in certain geographic regions, such as Southwestern Taiwan, possibly due to environmental exposures or underlying genetic susceptibility (2). Radical nephroureterectomy (RNU) with excision of the bladder cuff remains the gold-standard treatment for high-risk localized UTUC, especially in cases presenting with multifocality, large tumor burden (>2 cm), high-grade histology or advanced clinical stage at diagnosis (3–5). Postoperative management following RNU is guided by established prognostic indicators, including pathological stage, tumor grade, lymphovascular invasion and margin status, with adjuvant chemotherapy or salvage radiotherapy considered for patients at increased risk of recurrence or progression (6).

More recently, neoadjuvant chemotherapy has emerged as a potential strategy for selected patients with high-risk UTUC, aiming to optimize cisplatin eligibility prior to nephrectomy-induced renal function decline, while immune checkpoint inhibitors have shown promise in advanced and metastatic UC and are being explored in perioperative settings (7,8). However, despite these systemic treatment advances, their precise role in localized UTUC is still evolving, and robust preoperative biomarkers to guide patient selection are still lacking. As for adjuvant chemotherapy, platinum-based treatment was demonstrated to improve outcomes for patients with high-risk UTUC following RNU in the POUT trial (9). Hence, an increasing number of studies have been dedicated to discovering more reliable and feasible prognosticators for selecting high-risk patients who may truly benefit from adjuvant therapy.

Despite adherence to surgical guidelines, clinical outcomes in UTUC remain heterogeneous. Risk stratification after RNU typically incorporates established pathological factors such as tumor stage, grade, lymphovascular invasion (LVI) and surgical margin status (6). However, these parameters alone often fail to capture the broader immunological and systemic context influencing tumor progression. Consequently, recent efforts have turned toward identifying systemic biomarkers, particularly those linked to host immunity and inflammation, to improve prognostication (10–12).

Studies have highlighted the prognostic relevance of various systemic inflammatory markers in UTUC, including the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio and the systemic immune-inflammation index (10–13). Yet, their predictive precision remains limited. Given the immune-mediated nature of cancer progression, a more integrated approach involving immune organ metrics may enhance clinical risk models.

The spleen, as the largest secondary lymphoid organ and a key component of the reticuloendothelial system, plays a central role in both innate and adaptive immunity (14). Emerging evidence suggests that immune dysregulation, manifesting as splenic enlargement due to the accumulation of immune cells, may influence oncological outcomes in various malignancies, including hepatocellular carcinoma (HCC), colorectal cancer and lung cancer (15–18). In particular, the spleen has been implicated in the production and mobilization of tumor-associated macrophages, tumor-associated neutrophils and myeloid-derived suppressor cells (MDSCs), all of which contribute to tumor immune evasion and progression (19). Clinical studies in diverse cancer types, including HCC, colorectal cancer and lung cancer, have suggested that increased splenic volume (SV) may correlate with immune suppression and a poor prognosis, possibly mediated through depletion of cytotoxic lymphocyte subsets such as CD4⁺ T cells and natural killer cells (16–18,20,21).

To date, no study has systematically examined the prognostic relevance of SV or its interplay with circulating lymphocyte parameters in UTUC. Therefore, the current study aimed to explore the independent and synergistic prognostic value of baseline standardized SV and lymphocyte percentage (lym%) in patients with non-metastatic UTUC undergoing RNU.

In the present retrospective cohort study of 465 patients with non-metastatic UTUC who underwent RNU, a higher preoperative SV and lower peripheral lym% were found to be independently associated with inferior OS, CSS and MFS. Notably, the combined presence of high SV and low lym% was the strongest prognostic indicator across all endpoints. These findings suggest that baseline immune and hematological parameters, quantified through imaging and routine blood tests, may offer valuable insights into host-tumor dynamics and support individualized risk stratification.

The present analysis expands on existing literature linking splenomegaly to adverse outcomes in solid malignancies. Prior studies have demonstrated that elevated SV is associated with a poor prognosis in hepatocellular carcinoma, pancreatic cancer, gastric cancer, metastatic colorectal cancer and non-small cell lung cancer (17,20,21,24). Consistent with these observations, the present study found that larger baseline SV predicted worse oncological outcomes in UTUC. Importantly, to the best of our knowledge, the present study is the first to evaluate SV in the context of urothelial carcinoma of the upper tract and to integrate peripheral immune status (lym%) as a complementary biomarker.

While the mechanistic link between splenic remodeling and cancer outcomes remains under investigation, accumulating evidence from preclinical models supports the role of the spleen in tumor-induced immune suppression (23,25). Han et al (26) found that tumor-bearing mice produced erythroblast-like Ter cells in the spleen that promoted hepatocellular carcinoma progression. Additional studies by Zhao et al (27) and Sano et al (28) identified CD71⁺TER119⁺ erythroid progenitor cells in the spleen that exert immunosuppressive effects on effector T cells. Moreover, the spleen has been shown to facilitate the generation and expansion of MDSCs in the tumor-bearing state, further contributing to an immunosuppressive milieu and enhanced tumor aggressiveness (23,29,30). Jiang et al (31) demonstrated a positive correlation between splenic weight and serum mMDSC levels in a mouse model of hepatocellular carcinoma. The clinical relevance of these findings is underscored by the study by Levy et al (32), which demonstrated that splenectomy inhibited tumor growth and metastasis in non-small cell lung cancer by depleting MDSCs and enhancing cytotoxic T-cell activation. The present findings may therefore reflect a broader impairment of systemic immunity in UTUC. An enlarged spleen may indicate an activated yet functionally exhausted immune state, accompanied by peripheral lymphocyte depletion, diminished antitumor immune surveillance and a pro-inflammatory milieu. Additionally, tumor-stroma interactions likely amplify this process by promoting cytokine-driven immune evasion, neutrophil recruitment and microenvironmental immunosuppression (17,19,29). Together, these mechanisms offer a biological explanation for why patients with high standardized SV and low circulating lym% are prone to early metastasis and inferior oncological outcomes.

The combination of imaging-derived SV and routine lym% may serve as a non-invasive, cost-effective method for identifying high-risk patients with UTUC who might benefit from intensified surveillance or consideration of adjuvant systemic therapies. Given the lack of robust predictive biomarkers in this population, the present results provide a potentially actionable stratification tool that complements established clinicopathological factors such as stage, LVI and nodal status.

Nevertheless, several limitations warrant consideration. First, the retrospective nature and single-center design of the present study may introduce selection bias and limit generalizability. Second, the study was lacking post-operative immune profiling or longitudinal SV measurements, which restricts the ability to evaluate dynamic immunological changes over time. Finally, although ROC-based cutoffs were used to dichotomize SV and lym%, external validation of these thresholds is necessary before clinical application.

In conclusion, higher standardized SV combined with lower circulating lym% was identified as a novel, independent predictor of worse survival outcomes in patients with UTUC following RNU. These findings suggest that incorporating baseline standardized SV and lym%, alongside established clinicopathological risk factors, can enhance risk stratification and support more individualized postoperative management strategies.