在黑色素瘤中，迫切需要新的治疗方法，尤其是对免疫疗法和激酶抑制剂无反应的晚期患者。为了发现T细胞抗肿瘤免疫力的新潜能，我们进行了一项离体药物筛选，并确定了5-壬氧色胺（5-NL）作为一种增强T细胞靶向肿瘤细胞能力的血清素激动剂。药物筛选利用淋巴细胞性脑膜炎病毒（LCMV）免疫灌注的脾脏T细胞和表达LCMV gp33 CTL表位的黑色素瘤B16.F10细胞。我们采用C57BL/6 J和NSG小鼠的体内肿瘤生长、体内抗体耗尽、流式细胞术、免疫印迹、CRISPR/Cas9基因敲除、组织学和RNA-Seq分析来解析5-NL在体内外的免疫调节效应。5-NL延缓了体内肿瘤的生长，并且其表型依赖于宿主的免疫系统，特别是CD8+ T细胞。 5-NL的亲免疫效应与T细胞无直接关系。相反，5-NL在体内外上调了黑色素瘤和其他肿瘤细胞的抗原递呈机制，而不增加PD-L1的表达。机制研究表明，5-NL诱导的MHC-I表达受到了抑制性cAMP反应元件结合蛋白（CREB）磷酸化的药物抑制。重要的是，与单独应用抗PD1治疗相比，5-NL结合抗PD1治疗在疗效方面显示出显著的改善。这项研究展示了在免疫原性较差的肿瘤中增强免疫应答的新治疗机会。© 2023年 BioMed Central Ltd., Springer Nature旗下的一部分。

New therapies are urgently needed in melanoma, particularly in late-stage patients not responsive to immunotherapies and kinase inhibitors. To uncover novel potentiators of T cell anti-tumor immunity, we carried out an ex vivo pharmacological screen and identified 5-Nonyloxytryptamine (5-NL), a serotonin agonist, as increasing the ability of T cells to target tumor cells.The pharmacological screen utilized lymphocytic choriomeningitis virus (LCMV)-primed splenic T cells and melanoma B16.F10 cells expressing the LCMV gp33 CTL epitope. In vivo tumor growth in C57BL/6 J and NSG mice, in vivo antibody depletion, flow cytometry, immunoblot, CRISPR/Cas9 knockout, histological and RNA-Seq analyses were used to decipher 5-NL's immunomodulatory effects in vitro and in vivo.5-NL delayed tumor growth in vivo and the phenotype was dependent on the hosts' immune system, specifically CD8+ T cells. 5-NL's pro-immune effects were not directly consequential to T cells. Rather, 5-NL upregulated antigen presenting machinery in melanoma and other tumor cells in vitro and in vivo without increasing PD-L1 expression. Mechanistic studies indicated that 5-NL's induced MHC-I expression was inhibited by pharmacologically preventing cAMP Response Element-Binding Protein (CREB) phosphorylation. Importantly, 5-NL combined with anti-PD1 therapy showed significant improvement when compared to single anti-PD-1 treatment.This study demonstrates novel therapeutic opportunities for augmenting immune responses in poorly immunogenic tumors.© 2023. BioMed Central Ltd., part of Springer Nature.