Xingang Guan

T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) is an inhibitory receptor expressed on immune cells, and its co-expression with programmed cell death protein 1 (PD-1) is an established mechanism of immune exhaustion and resistance to checkpoint blockade. To overcome this, we developed PD-1/Tim-3-decorated nanovesicles (PD-1/Tim-3 NVs) for combination immunotherapy against colorectal cancer. These vesicles selectively engaged the ligands PD-L1 and Galectin-9. In mice bearing CT26 xenografts, PD-1/Tim-3 NVs suppressed tumor growth by 69.0%, remodeled the tumor microenvironment by enhancing CD8 ⁺ T cell infiltration and activation, and depleting immunosuppressive regulatory T cells. Our findings highlight the promising potential of simultaneous PD-1 and Tim-3 blockade for treating advanced tumors.

Cullin4B (CUL4B), which functions as a scaffold protein within the CUL4B-RING ubiquitin ligase complex (CRL4B), is frequently overexpressed in various cancers and exhibits oncogenic characteristics. However, its specific role in hepatocellular carcinoma (HCC) progression and drug resistance remains unclear. This study revealed that CUL4B is upregulated in HCC tissues, with elevated levels correlating with poor patient prognosis. A strong inverse relationship was observed between the expression of CUL4B and the tumor suppressor miR-143-3p in human HCC samples; CUL4B knockdown significantly increased miR-143-3p levels. Moreover, suppression of CUL4B inhibited HCC cell proliferation and enhanced sensitivity to oxaliplatin through miR-143-3p upregulation. Fused in sarcoma (FUS), an RNA-binding protein implicated in miRNA biogenesis, was identified as a novel CRL4B ^DTL substrate. CUL4B facilitates FUS ubiquitination and subsequent degradation, thereby reducing FUS protein levels. This reduction impairs miR-143-3p formation, activates the KRAS signaling pathway, and promotes tumor progression and oxaliplatin resistance. In summary, this study provided compelling evidence that CUL4B knockdown may be a promising strategy for treating HCC and increasing tumor cell sensitivity to oxaliplatin therapy.

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable success in treating various types of solid tumors; however, only a limited number of patients currently benefit from these therapeutic agents. Developing novel ICIs that elicit systemic and durable antitumor immune responses remains a significant challenge in improving immunotherapy outcomes. In this study, we engineered PD-1/LAG-3 receptors onto cell membrane nanovesicles to simultaneously block two immune checkpoints for the treatment of colorectal cancer. This dual-checkpoint blockade strategy led to significantly more potent tumor growth suppression in mice with MC38 xenografts compared to nanovesicles targeting PD-1 or LAG-3 alone. Notably, the hybrid nanovesicles substantially rejuvenated exhausted CD8⁺ T cells, promoting dendritic cell maturation and depleting regulatory T cells (Tregs). This research highlights the promising potential of cell membrane nanovesicles as an effective platform for delivering multiple immune checkpoints in cancer immunotherapy, offering a novel strategy to enhance therapeutic efficacy.

Immune checkpoint inhibitors (ICIs) have shown unprecedented efficacy in treating many advanced cancers. Although FDA-approved ICIs have shown promising efficacy in treating many advanced cancers, their application is greatly limited by the low response rate, immune-related adverse events (irAE), and drug resistance. Developing novel ICIs holds great promise to improve the survival and prognosis of advanced cancer patients. T-Cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on T cells, natural killer (NK) cells, and T regulatory cells. Increasing reports have shown that the disrupting CD155-TIGIT axis could activate the immune system and restore antitumor immune response. This review briefly summarized the role of TIGIT in tumor immune escape and targeting CD155-TIGIT axis drugs in preclinical and clinical trials for cancer immunotherapy.

Cancer cells have adapted to rapid tumor growth and evade immune attack by reprogramming their metabolic pathways. Glutamine is an important nitrogen resource for synthesizing amino acids and nucleotides and an important carbon source in the tricarboxylic acid (TCA) cycle and lipid biosynthesis pathway. In this review, we summarize the significant role of glutamine metabolism in tumor development and highlight the vulnerabilities of targeting glutamine metabolism for effective therapy. In particular, we review the reported drugs targeting glutaminase and glutamine uptake for efficient cancer treatment. Moreover, we discuss the current clinical test about targeting glutamine metabolism and the prospective direction of drug development.