Cisplatin (DDP)-based chemoradiotherapy is one of the standard treatments for nasopharyngeal carcinoma (NPC). However, the sensitivity and side effects of DDP to patients remain major obstacles for NPC treatment. This research aimed to study DDP sensitivity regulated by cancer-associated fibroblasts (CAFs) through modulating ferroptosis. We demonstrated that DDP triggered ferroptosis in NPC cells, and it inhibited tumor growth via inducing ferroptosis in xenograft model. CAFs secreted high level of FGF5, thus inhibiting DDP-induced ferroptosis in NPC cells. Mechanistically, FGF5 secreted by CAFs directly bound to FGFR2 in NPC cells, leading to the activation of Keap1/Nrf2/HO-1 signaling. Rescued experiments indicated that FGFR2 overexpression inhibited DDP-induced ferroptosis, and CAFs protected against DDP-induced ferroptosis via FGF5/FGFR2 axis in NPC cells. In vivo data further showed the protective effects of FGF5 on DDP-triggered ferroptosis in NPC xenograft model. In conclusion, CAFs inhibited ferroptosis to decrease DDP sensitivity in NPC through secreting FGF5 and activating downstream FGFR2/Nrf2 signaling. The therapeutic strategy targeting FGF5/FGFR2 axis from CAFs might augment DDP sensitivity, thus decreasing the side effects of DDP in NPC treatment.

Reprogramming of macrophages toward an M1 phenotype is a novel strategy to induce anticancer immunity. However, the regulatory mechanisms of M1 macrophage polarization and its functional roles in nasopharyngeal carcinoma (NPC) progression need to be further explored. Here we found that SPLUNC1 was highly expressed and responsible for M1 macrophage polarization. JAK/STATs pathway activation was involved in SPLUNC1-mediated M1 macrophage polarization. Importantly, regulation of SPLUNC1 in macrophages affected CM-mediated influence on NPC cell proliferation and migration. Mechanistically, USP7 deubiquitinated and stabilized TRIM24, which promoted SPLUNC1 expression via recruitment of STAT3 in M1 macrophages. Depletion of TRIM24 inhibited M1 macrophage polarization, which facilitated NPC cell growth and migration. However, over-expression of USP7 exhibited the opposite results and counteracted the tumorigenic effect of TRIM24 silencing. Finally, the growth and metastasis of NPC cells in vivo were repressed by USP7-induced M1 macrophage polarization via modulating TRIM24/SPLUNC1 axis. USP7 delayed NPC progression via promoting macrophage polarization toward M1 through regulating TRIM24/SPLUNC1 pathway, providing evidence for the development of effective antitumor immunotherapies for NPC.

Background: Reliable biomarkers for risk stratification and treatment monitoring in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC) treated with first-line chemo-immunotherapy remain limited. This study evaluated the prognostic value of baseline computed tomography (CT)-derived body composition parameters and their early dynamic changes. Methods: In this single-center retrospective cohort study, patients with R/M NPC receiving first-line chemo-immunotherapy were included. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Associations between body composition and outcomes were analyzed. Results: A total of 199 patients were included, and 99 with post-treatment CT after 2 cycles were further analyzed for dynamic changes. Higher baseline skeletal muscle area (SMA) was independently associated with longer PFS (HR = 0.56; 95% CI, 0.37-0.85; P = 0.006) and OS (HR = 0.46; 95% CI, 0.23-0.93; P = 0.03), and with higher ORR (82.8% vs 70.0%; P = 0.033) and DCR (98.0% vs 91.0%; P = .031). During early treatment, a ≤1.3% decrease or an increase in SMA was independently associated with longer PFS (HR = 0.53; P = 0.045) and OS (HR = 0.27; P = 0.018). A greater decline in visceral adipose tissue density (ΔVATD < −0.9%) was also associated with more favorable PFS and OS, whereas no significant difference in ORR was observed. Conclusion: Baseline SMA and early changes in SMA and VATD have prognostic value in R/M NPC treated with first-line chemo-immunotherapy. CT-based body composition assessment may serve as a practical imaging biomarker for risk re-stratification and individualized management.

Background The timing of immunotherapy administration has been linked to variations in clinical outcome across multiple cancers, but its effect on clinical outcome in nasopharyngeal carcinoma (NPC) remains unstudied. Methods In this single-center retrospective cohort study, patients with recurrent/metastatic (R/M) NPC who received first-line anti-PD-1-based immunochemotherapy (June 2019–December 2024) were included. The primary endpoint was progression-free survival (PFS), and overall survival (OS) was the secondary endpoint. Data regarding the time of day of administration (ToDA) during the initial four cycles were collected for each patient. Survival was estimated by the Kaplan–Meier method and compared with log-rank tests. Multivariable Cox models were adjusted for prespecified covariates. Propensity score matching (PSM) was performed between patients from different ToDA groups. The ToDA cutoff was derived from the data without a prespecified hypothesis, using a data-driven approach. Results Among the 334 screened patients, 312 met the eligibility criteria. The median follow-up was 24.9 months. The median PFS was 25.0 months, and the mOS was not reached. A data-driven optimal ToDA cutoff of 12:00 was identified. Patients who received immunotherapy after 12:00 had significantly longer PFS (31.2 vs. 18.3 months, p = 0.006) and OS (both not reached, p = 0.011). After PSM at a 1:2 ratio, PFS (36.1 vs. 18.3 months, p = 0.003) and OS (both not reached, p = 0.018) were still significantly improved in patients who received immunotherapy after 12:00. Multivariate analysis demonstrated that a ToDA after 12:00 was independently correlated with improved PFS (HR=0.63; 95% CI: 0.43-0.92; p = 0.017) and OS (HR=0.48; 95% CI: 0.27–0.84; p = 0.010). Conclusions These hypothesis-generating findings suggest that, in R/M NPC patients treated with first-line immunochemotherapy, afternoon administration during the initial four cycles may be associated with improved PFS and OS. However, because the ToDA threshold was selected post hoc, the results should be interpreted with caution. Randomized clinical trials are warranted to validate these findings.