肿瘤细胞治疗研究
英文原题：Innate immune dysregulation in multiple myeloma: molecular basis and mechanistic interventions.
先天免疫应被视为MM发病机制和治疗的核心组成部分，而非次要因素。对先天免疫失调机制的深入理解，不仅可能完善当前的免疫治疗策略，还可能启发新的治疗范式，最终改善MM的长期疾病控制。
多发性骨髓瘤（MM）是一种起源于骨髓浆细胞的恶性克隆性疾病。尽管蛋白酶体抑制剂、免疫调节剂、单克隆抗体和细胞免疫疗法的引入显著延长了患者的生存期，但复发和耐药几乎不可避免，使得MM在很大程度上仍无法治愈。既往研究主要强调克隆演化和适应性免疫功能障碍，而固有免疫在MM发生和进展中的贡献相对被低估。 主要内容：越来越多的证据表明，固有免疫细胞在重塑骨髓微环境和建立多发性骨髓瘤免疫耐受中发挥关键作用。本综述系统总结了关键固有免疫细胞群的功能改变，包括NK 细胞、恒定自然杀伤T细胞、树突状细胞、髓源性抑制细胞和肿瘤相关巨噬细胞。这些细胞的数量失衡、功能耗竭和表型极化共同损害免疫监视，从而促进免疫逃逸、治疗耐药和髓外播散。此外，靶向固有免疫的新兴治疗策略，如免疫检查点阻断、代谢重编程、细胞因子调节以及工程化NK 细胞或恒定自然杀伤T细胞疗法，正受到越来越多的关注。与此同时，肠道来源代谢物对固有免疫功能的调控揭示了具有转化潜力的额外免疫调节机制。
BACKGROUND: Multiple myeloma (MM) is a malignant clonal disorder originating from bone marrow plasma cells. Although the introduction of proteasome inhibitors, immunomodulatory agents, monoclonal antibodies, and cellular immunotherapies has markedly prolonged patient survival, relapse and drug resistance remain almost inevitable, rendering MM largely incurable. Previous research has predominantly emphasized clonal evolution and adaptive immune dysfunction, whereas the contribution of innate immunity to MM initiation and progression has been comparatively underappreciated. MAIN BODY: Accumulating evidence indicates that innate immune cells play pivotal roles in reshaping the bone marrow microenvironment and establishing immune tolerance in multiple myeloma. This review systematically summarizes the functional alterations of key innate immune populations, including natural killer cells, invariant natural killer T cells, dendritic cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Numerical imbalances, functional exhaustion, and phenotypic polarization of these cells collectively impair immune surveillance, thereby facilitating immune evasion, therapeutic resistance, and extramedullary dissemination. Moreover, emerging therapeutic strategies targeting innate immunity, such as immune checkpoint blockade, metabolic reprogramming, cytokine modulation, and engineered natural killer or invariant natural killer T cell therapies, are gaining increasing attention. In parallel, regulation of innate immune function by gut-derived metabolites has revealed an additional layer of immunomodulatory mechanisms with translational potential. CONCLUSIONS: Innate immunity should be regarded as a central component in the pathogenesis and treatment of MM rather than a secondary contributor. A deeper mechanistic understanding of innate immune dysregulation may not only refine current immunotherapeutic strategies but also inspire novel therapeutic paradigms, ultimately improving long-term disease control in MM.
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