Growing evidence suggests that cisplatin and other chemotherapeutic agents promote tumor metastasis while inhibiting tumor growth, which is a critical issue for certain patients in clinical practices. However, the role of chemotherapeutics in promoting tumor metastasis and the molecular mechanism involved are unclear. Here, we investigated the roles of cisplatin in promoting tumor metastasis in lung adenocarcinoma (LUAD). We demonstrated that cisplatin promoted epithelial-mesenchymal transition (EMT), cell motility, and metastasis in vitro and in vivo. The bioinformatic analysis and molecular biology approaches also indicated that DCBLD2 (Discoidin, CUB and LCCL domain containing 2) is a key gene that mediates cisplatin-induced metastasis. DCBLD2 stabilizes β-catenin by phosphorylating GSK3β and transporting accumulated β-catenin to the nucleus to promote the expression of EMT-related transcriptional factors (TFs), ultimately resulting in tumor metastasis. We also identified that cisplatin enhanced DCBLD2 expression by phosphorylating ERK and hence the AP-1-driven transcription of DCBLD2. Furthermore, DCBLD2-specific siRNAs encapsulated by nanocarriers prominently inhibit cisplatin-induced metastasis in vivo. Therefore, DCBLD2 plays a key role in cisplatin-induced metastasis in LUAD and is a potential target for preventing chemotherapy-induced metastasis in vivo.

A novel series of pyrimidine-benzotriazole derivatives have been synthesized and evaluated for their anticancer activity against human solid tumor cell lines. The most promising molecule 12O was identified for its excellent antiproliferative activities, especially against the SiHa cell line with IC₅₀ value as 0.009 μM. Kinase inhibition assay assessed 12O was a potential multi-kinase inhibitor, which possessed potent inhibitory activities against cyclin-dependent kinases (CDKs) and fms-like tyrosine kinase (FLT) with IC₅₀ values in the nanomolar range. Molecular docking studies illustrated that the introduction of triazole moiety in 12O was critical for CDKs inhibition. In addition, 12O inhibited cancer cell proliferation, colony-formation, and cell cycle progression and provoked apoptotic death in vitro. In an SiHa xenograft mouse model, a once-daily dose of compound 12O at 20 mg/kg significantly suppressed the tumor growth without obvious toxicity. Taken together, 12O provided valuable guide for further structural optimization for CDKs and FLT inhibitors.

SUMMARY: Resistance to immune checkpoint inhibition remains a major barrier in pancreatic cancer treatment. Here, we show that concurrent administration of probiotics restores sensitivity to anti-PD-1 therapy in pancreatic cancer mouse models. Mice treated with the combination of anti-PD-1 and probiotics demonstrate robust tumor control, accompanied by enrichment of microbial pathways governing cysteine biosynthesis, elevated serum cysteine levels, and increased T cell function. Serum cysteine levels, rather than intratumoral cysteine concentrations, inversely correlate with tumor burden. Functionally, cysteine directly promotes T cell survival, activation, and cytotoxicity while its restriction induces uncoupled transcriptional-translational stress and impairs T cell function. Oral cysteine supplementation synergizes with anti-PD-1 therapy in pancreatic cancer mice, reducing tumor burden and enhancing intratumoral T cell activation, phenocopying probiotics-mediated immune restoration. These findings suggest systemic cysteine availability as a tractable metabolic target to enhance cancer immunotherapy.

To investigate the roles of the α2,3-sialyltransferase ST3Gal1 and the α2,6-sialyltransferase ST6Gal1 in T cell-mediated tumor control, we generated mice with mature T cell-specific deletion of ST3Gal1 (T-ST3KO) or ST6Gal1 (T-ST6KO) using distal Lck-Cre-mediated recombination. Deletion of ST3Gal1 in mature T cells did not affect thymic T cell development but resulted in a reduction of peripheral CD8+ T cells. In contrast, ST6Gal1 deletion had minimal impact on T cell development and peripheral T cell abundance. Following in vitro stimulation of isolated T cells from T-ST3KO and parental wild type (WT) mice with anti-CD3 plus anti-CD28/CD80-Fc, CD8+ T cells from T-ST3KO mice exhibited enhanced activation and an increased frequency of CD44 positive memory-like T cells, while comparison of T cells from T-ST6KO and the parental WT mice showed no significant changes. Despite the activated CD8+ T cell phenotype in T-ST3KO mice, subcutaneous MC38 tumors displayed accelerated growth. In contrast, tumor progression in T-ST6KO mice was unchanged from the parental WT mice. Notably, T-ST6KO mice developed increased pulmonary metastases following intravenous challenge with B16F10 melanoma cells, whereas metastatic burden was unaffected in T-ST3KO mice. These findings demonstrate distinct and non-redundant roles for ST3Gal1- and ST6Gal1-mediated sialylation in regulating T cell function and antitumor immunity and reveal context-dependent effects of T cell intrinsic sialylation in controlling primary tumor growth and metastatic dissemination.

Systemic inflammation is increasingly recognized as a contributor to neuroinflammation and neurodegenerative disease progression. Periodontitis, a chronic