肿瘤细胞治疗研究
英文原题：Systemic administration of Photobacterium angustum promotes antitumor immunity and direct tumor lysis in murine models of colorectal cancer.
我们的研究结果支持P. angustum作为一种有前景的结直肠癌细菌免疫治疗平台，其结合了肿瘤特异性定植、免疫激活和直接杀瘤效应，并具有出色的安全性。
尽管癌症免疫治疗取得了显著进展，包括免疫检查点抑制剂和过继性细胞疗法，但许多患者由于免疫抑制性肿瘤微环境、肿瘤抗原性差和全身毒性等因素而未能实现持久缓解。这些局限性凸显了对能够引发强效且局部化抗肿瘤免疫反应的替代平台的需求。细菌因其天然具备选择性定植肿瘤、刺激先天性和适应性免疫以及可被工程化用于治疗性递送的能力，已成为有前景的候选者。然而，天然存在的海洋细菌菌株在结直肠癌中的治疗潜力在很大程度上仍未被探索。
我们在结直肠癌的同基因和原位小鼠模型中筛选了一组海洋细菌菌株的抗肿瘤活性。基于其强效抗肿瘤作用，选择了 Photobacterium angustum。我们评估了静脉给药后的肿瘤定植、全身毒性和免疫反应。通过血清细胞因子谱分析和血液学分析评估了生物安全性。通过定量 PCR 和免疫组织化学检查了免疫激活。
P. angustum 治疗显著延长了荷瘤小鼠的生存期，并表现出强烈的肿瘤趋向性，对健康组织的定植极少。全身给药耐受良好，促炎细胞因子水平低，无血液学毒性。治疗增强了肿瘤微环境中 T 细胞、B 细胞和中性粒细胞的浸润，伴随瘤内肿瘤坏死因子-α和干扰素-γ水平升高。此外，P. angustum 表现出内在的溶瘤活性，有助于直接裂解肿瘤细胞。
BACKGROUND: Despite remarkable advances in cancer immunotherapy, including immune checkpoint inhibitors and adoptive cell therapies, many patients fail to achieve durable responses due to factors such as immunosuppressive tumor microenvironments, poor tumor antigenicity, and systemic toxicity. These limitations underscore the need for alternative platforms that can elicit robust and localized antitumor immune responses. Bacteria have emerged as promising candidates owing to their natural ability to selectively colonize tumors, stimulate innate and adaptive immunity, and be engineered for therapeutic delivery. However, the therapeutic potential of naturally occurring marine bacterial strains remains largely unexplored in colorectal cancer. METHODS: We screened a panel of marine bacterial strains for antitumor activity in syngeneic and orthotopic mouse models of colorectal cancer. Photobacterium angustum was selected based on its potent antitumor effects. We evaluated tumor colonization, systemic toxicity, and immune responses following intravenous administration. Biosafety was assessed via serum cytokine profiling and hematological analysis. Immune activation was examined by quantitative PCR and immunohistochemistry. RESULTS: P. angustum therapy significantly prolonged survival in tumor-bearing mice and exhibited strong tumor tropism with minimal colonization of healthy tissues. Systemic administration was well tolerated, with low levels of pro-inflammatory cytokines and no hematological toxicity. Treatment enhanced infiltration of T cells, B cells, and neutrophils in the tumor microenvironment, accompanied by elevated intratumoral tumor necrosis factor-α and interferon-γ levels. Additionally, P. angustum demonstrated intrinsic oncolytic activity, contributing to direct tumor cell lysis. CONCLUSIONS: Our findings support P. angustum as a promising platform for bacterial immunotherapy in colorectal cancer, combining tumor-specific colonization, immune activation, and direct tumoricidal effects with an excellent safety profile.
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