6-Phosphofructo 2-kinase/fructose 2, 6-bisphosphatase 3 (PFKFB3) has been reported to be overexpressed in human cancer tissues and to promote the proliferation and migration of cancer cells. However, the role of PFKFB3 in the progression and prognosis of breast cancer is not yet fully understood. In the present study, we investigated the specific role of PFKFB3 in breast cancer progression and its preliminary mechanisms of action. We first used an immunohistochemistry assay to determine that PFKFB3 was highly expressed in breast cancer tissues and that this high level of expression was involved in the poor overall survival of patients with breast cancer. In addition, the suppression of PFKFB3 by lentiviruses carrying shRNA against PFKFB3 (shPFKFB3) subsequently inhibited breast cancer cell (MDA-MB-231 and MDA-MB-468) proliferation, migration and invasion, and induced cell cycle G1 and S phase arrest in vitro. Moreover, PFKFB3 inhibition decreased p-AKT and increased p27 expression levels in breast cancer cells. Furthermore, PFKFB3 suppression inhibited breast cancer cell tumor xenograft growth in nude mice. We also found that PFKFB3 inhibition suppressed vascular endothelial growth factor α (VEGFα) protein expression and inhibited the angiogenic activity of human umbilical vein endothelial cells (HUVECs). On the whole, our results indicate that PFKFB3 is involved in the proliferation, migration, invasion and angiogenesis of breast cancer.

Background: For patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC), concurrent chemoradiotherapy (CCRT) is the current standard treatment; however, the prognosis remains poor. Immunotherapy combined with chemotherapy has demonstrated improved survival outcomes in advanced ESCC. Nevertheless, there is a lack of reports on the role of induction immunotherapy plus chemotherapy prior to CCRT for unresectable locally advanced ESCC. Therefore, this study aimed to evaluate the efficacy and safety of induction immunotherapy plus chemotherapy followed by definitive chemoradiotherapy in patients with unresectable locally advanced ESCC. Methods: This study retrospectively collected clinical data of patients diagnosed with locally advanced ESCC who were treated with radical CCRT between 2017 and 2021 at our institution. The patients were divided into two groups: an induction immunotherapy plus chemotherapy group (induction IC group) or a CCRT group. To assess progression-free survival (PFS) and overall survival (OS), we employed the Kaplan–Meier method after conducting propensity score matching (PSM). Results: A total of 132 patients with unresectable locally advanced ESCC were included in this study, with 61 (45.26%) patients in the induction IC group and 71 (54.74%) patients in the CCRT group. With a median follow-up of 37.0 months, median PFS and OS were 25.2 and 39.2 months, respectively. The patients in the induction IC group exhibited a significant improvement in PFS and OS in comparison with those in the CCRT group (median PFS: not reached [NR] versus 15.9 months, hazard ratio [HR] 0.526 [95%CI 0.325–0.851], P = 0.0077; median OS: NR versus 25.2 months, HR 0.412 [95%CI 0.236–0.719], P = 0.0012). After PSM (50 pairs), both PFS and OS remained superior in the induction IC group compared to the CCRT group (HR 0.490 [95%CI 0.280–0.858], P = 0.011; HR 0.454 [95%CI 0.246–0.837], P = 0.0093), with 2-year PFS rates of 67.6 and 42.0%, and the 2-year OS rates of 74.6 and 52.0%, respectively. Multivariate analysis revealed that lower tumor stage, concurrent chemotherapy using double agents, and induction immunotherapy plus chemotherapy before CCRT were associated with better prognosis. Conclusions: Our results showed for the first time that induction immunotherapy plus chemotherapy followed by CCRT for unresectable locally advanced ESCC provided a survival benefit with manageable safety profile. More prospective clinical studies should be warranted.

Radiotherapy for head and neck cancer can cause serious side effects, including severe damage to the salivary glands, resulting in symptoms such as xerostomia, dental caries, and oral infection. Because of the lack of long-term treatment for the symptoms of xerostomia, current research has focused on finding endogenous stem cells that can differentiate into various cell lineages to replace lost tissues and restore functions. Here, we report that Sox9⁺ cells can differentiate into various salivary epithelial cell lineages under homeostatic conditions. After ablating Sox9⁺ cells, the salivary glands of irradiated mice showed more severe phenotypes and the reduced proliferative capacity. Analysis of online single-cell RNA-sequencing data reveals the enrichment of the Wnt/β-catenin pathway in the Sox9⁺ cell population. Furthermore, treatment with a Wnt/β-catenin inhibitor in irradiated mice inhibits the regenerative capability of Sox9⁺ cells. Finally, we show that Sox9⁺ cells are capable of forming organoids in vitro and that transplanting these organoids into salivary glands after radiation partially restored salivary gland functions. These results suggest that regenerative therapy targeting Sox9⁺ cells is a promising approach to treat radiation-induced salivary gland injury.

Due to the unsatisfactory robustness of current predictive biomarkers in many cases, application of immunotherapy in advanced cancers with limited treatment options, such as stage IV intrahepatic cholangiocarcinoma (ICC), was quite common. Hence, strategies to enhance the therapeutic effect of immunotherapy or to extend the scope of potential beneficial patients were urgently needed. Combination of radiotherapy and anti-programmed death receptor-1 (PD-1) immunotherapy was a promising one, since they were found to have a synergistic anti-tumor effect in animal models and a couple of patients. We here present a 68-years-old male with chemotherapy-intolerable stage IV ICC, whose primary tumor had low PD-L1 expression level, scarce CD8+ cells in tumor microenvironment, high microsatellite instability (MSI), and high tumor mutation burden (TMB). These biomarkers showed a conflicting prediction of the treatment response and clinical benefit of anti-PD-1 immunotherapy. Combination therapy of anti-PD-1 immunotherapy and radiotherapy was adopted as first-line treatment for the patient. After six cycles of immunotherapy, shrinkage of the primary liver tumor and metastatic lymph nodes happened, alongside with new lung metastasis, which indicated a mixed response. Radiotherapy was then administered to both the liver and lung lesions, accompanied with continued immunotherapy. The combined therapy eventually led to a complete response for both the primary tumor and all metastases without treatment-related adverse effects. The patient has survived for 26 months after the combined therapy and remains tumor-free currently. This case demonstrates the high inconsistency between immunotherapy response biomarkers and the synergetic anti-tumor effect of immunotherapy and radiotherapy in ICC.

PURPOSE: To evaluate the efficacy and safety of adding tislelizumab to induction chemotherapy and concurrent chemoradiotherapy (CRT), with or without maintenance immunotherapy, in patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: This multicenter, randomized, open-label, phase II trial was conducted across four academic hospitals in China (ClinicalTrials.gov identifier: NCT05520619 ). Participants were adults age 18-70 years with newly diagnosed, unresectable, stage II to IVB ESCC. Patients were randomly assigned (1:1) to receive two cycles of paclitaxel/cisplatin induction chemotherapy followed by concurrent CRT in combination with tislelizumab for 16 cycles in group A (two induction, two concurrent, and 12 maintenance) or four cycles in group B (two induction and two concurrent). The primary end point was progression-free survival (PFS) in the intention-to-treat population, compared with historical control. RESULTS: Between October 2022 and October 2024, 114 patients were randomly assigned to group A (n = 57) or group B (n = 57). After a median follow-up of 22.7 months (IQR, 16.2-28.2), group B demonstrated significantly better PFS versus controls (1-year: 71.9% [95% CI, 61.1 to 84.6] v 56.4% [95% CI, 44.7 to 71.1]; hazard ratio [HR], 0.54 [95% CI, 0.32 to 0.94]), while group A showed no PFS benefit (1-year: 52.6% [95% CI, 41.4 to 67.3]; HR, 1.06 [95% CI, 0.67 to 1.68]). Overall survival was also significantly better in group B (HR, 0.42 [95% CI, 0.22 to 0.82]). Grade ≥3 adverse events occurred in 86.0% of group A and 80.7% of group B, with the most common being lymphopenia (77.2% and 73.7%, respectively). Comprehensive biomarker analyses revealed that PD-L1 expression, CD8 ⁺ T-cell density, NRF2 pathway mutations, and dynamic changes in circulating tumor DNA were associated with treatment efficacy. CONCLUSION: The addition of tislelizumab to induction chemotherapy and concurrent CRT without maintenance immunotherapy demonstrated superior efficacy and manageable toxicity in locally advanced ESCC.