Urothelial carcinoma (UC) is characterized by a high incidence of TP53 mutation, and overcoming resistance to cisplatin-based chemotherapy in UC is a major concern. Wee1 is a G2/M phase regulator that controls the DNA damage response to chemotherapy in TP53-mutant cancers. The combination of Wee1 blockade with cisplatin has shown synergistic efficacy in several types of cancers, but little is known regarding UC. The antitumor efficacy of the Wee1 inhibitor (AZD-1775) alone or in combination with cisplatin was evaluated in UC cell lines and a xenograft mouse model. AZD-1775 enhanced the anticancer activity of cisplatin by increasing cellular apoptosis. AZD-1775 inhibited the G2/M checkpoint, improving the sensitivity of mutant TP53 UC cells to cisplatin by enhancing the DNA damage process. We confirmed that AZD-1775 combined with cisplatin reduced tumor volume and proliferation activity and increased the markers of cell apoptosis and DNA damage in the mouse xenograft model. In summary, the Wee1 inhibitor AZD-1775 combined with cisplatin elicited a promising anticancer efficacy in UC, and constitutes an innovative and promising therapeutic strategy.

Bladder cancer is a common cancer with well-established therapeutic strategies. However, recurrence occurs in 50% of patients with non-muscle-invasive bladder cancer, and 20% of patients progress to muscle-invasive bladder cancer. The 5-year survival rate for muscle-invasive bladder cancer patients is disappointingly low, ranging from 36% to 48%. A molecular marker of interest is chitinase 3-like-1 (CHI3L1), which is elevated in various cancers, including bladder cancer. In addition to its role in cancer cells, CHI3L1 also has regulatory abilities in immune cells. Neutrophil infiltration has been shown to positively correlate with overall survival, progression-free survival, and relapse-free survival in bladder cancer patients. However, the relationship between CHI3L1 and neutrophils remain poorly understood. Therefore, this study investigated the relationship between CHI3L1 level and protumor neutrophil infiltration in bladder cancer. We analyzed the GSE128959 dataset and the data of a bladder cancer cohort undergoing chemotherapy. We observed higher expression of CHI3L1 in bladder cancer patients with invasive or chemotherapy-resistance. Our results revealed a positive correlation between CHI3L1 expression and protumor neutrophil infiltration. Elevated CHI3L1 expression was associated with genes which were related to the recruitment and infiltration of neutrophils. Consequently, CHI3L1 may serve as a novel evaluation factor for the degree of neutrophil infiltration in advanced bladder cancer in those scheduled for chemotherapy.

Immune checkpoint inhibitors (ICIs) are widely used for first-line cisplatin-ineligible patients with metastatic urothelial carcinoma (mUC). However, whether to use ICIs as monotherapy or in combination with chemotherapy is still uncertain. We retrospectively analyzed cisplatin-ineligible patients with mUC who underwent first-line ICI monotherapy or ICI plus chemotherapy at 2 medical centers in Taiwan from 2016 to 2021. We calculated the objective response rate, progression-free survival, and overall survival (OS) using the Kaplan-Meier method and Cox regression model for multivariable analysis. In total, 130 patients were enrolled and categorized into 2 groups: an ICI monotherapy group [immunotherapy (IO), n=101] and an ICI plus noncisplatin chemotherapy group [immunotherapy and chemotherapy (IC), n=29]. The median OS of patients in the IO and IC groups was 19.5 and 9.7 months (P=0.33). Among patients with high programmed cell death ligand-1–expressing tumors, the median OS was significantly prolonged in the IO group compared with the IC group (not reached vs. 6.3 mo, P=0.02). First-line ICI monotherapy demonstrated robust antitumor activity in cisplatin-ineligible patients with mUC. Combining noncisplatin chemotherapy with ICI did not improve clinical outcomes.

Neutrophil extracellular trap formation (NETosis) has emerged as a pivotal regulator of the tumor immune microenvironment and a key determinant of response to cancer immunotherapy. NETs—web-like chromatin fibers decorated with histones, citrullinated histone H3, myeloperoxidase, neutrophil elastase, and matrix metalloproteinase-9—are induced by tumor-derived signals through classical lytic, vital non-lytic, and gasdermin D-dependent pathways, and exert context-dependent, predominantly pro-tumorigenic effects. Within the tumor microenvironment, NETs remodel the stroma, suppress CD8⁺ T-cell, natural killer-cell, and dendritic-cell function, promote regulatory T-cell and M2 macrophage polarization, and physically shield tumor cells from cytotoxic attack. By carrying programmed death-ligand 1 and driving T-cell exhaustion and immune exclusion, NETs compromise the efficacy of immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1, CTLA-4, and next-generation checkpoints, as well as adoptive cell therapies. This review synthesizes the molecular mechanisms of NETosis, its multifaceted immunomodulatory roles, and emerging NET-derived biomarkers—including MPO-DNA and citrullinated histone H3-DNA complexes—that may predict immunotherapy response and toxicity. We further appraise therapeutic strategies, including PAD4 inhibitors, DNase I, CXCR2 antagonists, and nanoparticle-based platforms, and underscore the need for standardized NET quantification, careful preservation of host defense, and biomarker-guided clinical trials to translate NET modulation into durable improvements in immunotherapy outcomes.

Purpose: Metastatic rectal cancer (mRC) is a highly lethal and complex disease that demands a multidisciplinary treatment approach. However, the clinical effectiveness of radiotherapy (RT) for de novo mRC remains controversial and uncertain.Methods: This retrospective cohort study examined medical records from Kaohsiung Chang Gung Memorial Hospital for patients with histologically confirmed de novo mRC diagnosed between January 2015 and December 2020. All patients received standard systemic therapy and radical surgery when feasible. The primary outcome, overall survival (OS), was assessed using the Kaplan-Meier method. Multivariable analysis was performed using a Cox regression model.Results: Among 271 patients included in the analysis, 117 received RT and 154 did not. The median OS was significantly longer in the RT group compared with the non-RT group (27.8 months vs. 21.9 months; P=0.046). Multivariate analysis identified several independent predictors of OS: age ≥65 years (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.26–2.27; P=0.001), primary tumor resection (HR, 2.62; 95% CI, 1.90–3.61; P<0.001), M1b or M1c disease (HR, 1.97; 95% CI, 1.44–2.69; P<0.001), and receipt of RT (HR, 1.41; 95% CI, 1.02–1.94; P=0.036).Conclusion: RT significantly improves OS in patients with mRC, underscoring its role in treatment strategies. These findings support its inclusion in therapeutic protocols and highlight the need for larger, multicenter trials to confirm and extend these results.

Cheung BH, et al. J Breast Cancer. 2026 ;29:e38. https://doi.org/10.4048/jbc.2026.0196