"Synergistic Suppression of Tumor Growth by Selenocystine and 5-Fluorouracil Through JAK/STAT Pathway Inhibition and Immune Checkpoint Regulation"

Abstract

Background: Liver cancer remains a major clinical challenge due to its aggressive progression and resistance to conventional therapies. The JAK-STAT signaling pathway and PD-1/PD-L1 immune checkpoint axis are key contributors to tumor growth and immune evasion.

Objective: This study aimed to evaluate the combined therapeutic effect of Selenium Cysteine (SeCys) and 5-Fluorouracil (5-FU) on tumor growth inhibition, immune modulation, and signaling pathway regulation in a preclinical liver cancer model.

Methods: We conducted an in vivo study with 250 subjects assigned to control, SeCys, 5-FU, or combination treatment groups. Tumor volumes, survival times, JAK-STAT pathway activation (pJAK2, pSTAT3), PD-L1 expression, and immune cell infiltration (CD8⁺ T-cells) were measured. Statistical analyses included ANOVA, Kruskal–Wallis tests, t-tests, Mann–Whitney U tests, and Pearson correlation.

Results: Combination therapy significantly inhibited tumor growth (mean TGI 50.82%, p < 0.0001), reduced pSTAT3 levels (χ² = 88.456, p < 0.0001), and increased PD-L1 mRNA expression (t = 8.399, p < 0.0001) compared to controls. CD8⁺ T-cell infiltration was enhanced in the combination group (p = 0.0465), and a strong inverse correlation was found between tumor growth inhibition and pSTAT3 levels (r = -0.881, p < 0.0001).

Conclusion: The synergistic effect of SeCys and 5-FU suppresses liver tumor progression through JAK-STAT pathway inhibition and immune checkpoint modulation, suggesting a novel therapeutic approach that integrates chemotherapy with immune activation. These findings warrant further investigation in humanized models and clinical trials to validate translational potential.