CCR3 modulators(Boehringer Ingelheim)

Studies have shown that the colonisation of active microorganisms is more conducive to the development of tumour immunotherapy, but intuitive evidence regarding shaping of the tumour immune microenvironment is lacking. In this study, we used Bifidobacterium longum subsp. longum (XZ01) to intervene in a colon cancer mouse model and found that its mechanism may be related to the interaction between the spatial distribution of microorganisms and tumour immunity. Through the visualisation method we established, for the first time, we showed that harmful active bacteria such as Streptococcus and Rhodococcus specifically accumulate in the middle and upper layers of tumour tissue. These bacteria likely participate in signalling pathways that affect macrophages by directly contacting or invading the macrophages, leading to a nondifferentiated state in macrophages and the loss of some immune functions. Furthermore, the accumulation of Streptococcus and Rhodococcus fragments in the deep layer of tumour tissue likely upregulates the expression of IL-10 in tumour tissue and inhibits other immune cells, such as CD8⁺ T cells, DC and NK cells. In contrast, XZ01 can specifically compete for the growth sites of Streptococcus and Rhodococcus in the middle and upper layers of tumour tissue and probably protects macrophages from being invaded by harmful bacteria. XZ01 directly regulates the polarisation of M0 macrophages towards the M1 phenotype by upregulating IFN-γ, thus activating tumour immunity to inhibit the growth of tumour cells. This study revealed that the influence of active microorganisms on the tumour immune microenvironment is crucial for effective immunotherapy intervention, potentially offering new targets for improving patient prognosis.

LSD1 (histone lysine-specific demethylase 1) has been gradually disclosed to act as an immunomodulator to enhance antitumor immune response. Despite the identification of numerous potent LSD1 inhibitors, there remains a lack of LSD1 inhibitors approved for marketing. Novel LSD1 inhibitors with different mechanisms are therefore needed. Herein, we reported a series of novel quinazoline-based LSD1 inhibitors. Among them, compound Z-1 exhibited the best LSD1 inhibitory activity (IC₅₀ = 0.108 μM). Z-1 also acted as a selective and cellular active as an LSD1 inhibitor. Furthermore, Z-1 promoted response of gastric cancer cells to T-cell killing effect by decreasing PD-L1 expression and further attenuated the PD-1/PD-L1 interaction. In vivo, Z-1 exhibited significant suppression effect on the growth of gastric cancer cells without obvious toxicity. Therefore, Z-1 represents a potential novel immunomodulator that targets LSD1, providing a lead compound with new function mechanism for gastric cancer treatment.