Advances in molecular targeted drugs in combination with CAR-T cell therapy for hematologic malignancies.

Molecular targeted drugs and chimeric antigen receptor (CAR) T cell therapy represent specific biological treatments that have significantly improved the efficacy of treating hematologic malignancies. However, they face challenges such as drug resistance and recurrence after treatment. Combining molecular targeted drugs and CAR-T cells could regulate immunity, improve tumor microenvironment (TME), promote cell apoptosis, and enhance sensitivity to tumor cell killing. This approach might provide a dual coordinated attack on cancer cells, effectively eliminating minimal residual disease and overcoming therapy resistance. Moreover, molecular targeted drugs can directly or indirectly enhance the anti-tumor effect of CAR-T cells by inducing tumor target antigen expression, reversing CAR-T cell exhaustion, and reducing CAR-T cell associated toxic side effects. Therefore, combining molecular targeted drugs with CAR-T cells is a promising and novel tactic for treating hematologic malignancies. In this review article, we focus on analyzing the mechanism of therapy resistance and its reversal of CAR-T cell therapy resistance, as well as the synergistic mechanism, safety, and future challenges in CAR-T cell therapy in combination with molecular targeted drugs. We aim to explore the benefits of this combination therapy for patients with hematologic malignancies and provide a rationale for subsequent clinical studies.

Stimulator of interferon genes from Asian swamp eel (MaSTING) is involved in host defense against bacterial infection.

Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER)-associated protein that plays critical roles in innate immunity and pathogenesis of various diseases. To date, teleost STING against viral stimulation has been identified, whereas STING signaling events in fish against bacteria are not well understood. In the present study, the open reading frame (ORF) of STING from Asian swamp eel (Monopterus albus) was cloned (named MaSTING) and its roles in bacterial infection were investigated. Amino acid sequence alignment and phylogenetic analysis revealed that MaSTING had conserved structures with mammalian STING and shared the closest relationship with mandarin fish STING. Subcellular localization analysis showed that MaSTING distributed in the whole cytoplasm and mainly co-localized with ER. Expression pattern analysis found that MaSTING was constitutively expressed in all the examined tissues with the highest expression in the liver and spleen. Post stimulation with bacteria and various PAMPs, the expression of MaSTING was induced at indicated time points in the immune-related organs and isolated peripheral blood leucocytes. Furthermore, the mechanism underlying MaSTING against bacterial infection was further studied. The qPCR analysis showed that MaSTING overexpression promoted 2'3'-cGAMP induced the expression of IFN-1, ISG15, Viperin, Mx, IL-1ß and TNF-α. Western blotting assay suggested that MaSTING significantly enhanced the phosphorylation of TANK-binding kinase 1 (TBK1) and p65. MaSTING also significantly increased the luciferase activity of IFN-1 and NF-κB promoters. Taken together, MaSTING is involved in host defense against bacterial infection by inducing the inflammatory response.