撰文丨王聪 编辑丨王多鱼 排版丨水成文 三阴性乳腺癌 （TNBC） 因缺乏雌激素受体 （ER） 、孕激素受体 （PR） 和 HER2 的表达而得名，是乳腺癌中最具侵袭性、最难治疗的亚型。近年来，免疫检 查点抑制剂 （ICI） 在 TNBC 治疗中展现出潜力，但仅部分患者受益。一个关键原因是肿瘤微环境 （TME） 的紊乱：免疫细胞被排除在肿瘤之外，无法有效攻 击癌细胞。 以往研究多聚焦于癌细胞本身或免疫细胞，但近年来，科学家们发现， 神经系统也参与肿瘤调控 。例如， 神经侵犯 （ Perineural Invasion ， PNI ） —— 癌细 胞包围、沿着或侵入神经纤维生长的想现象——与乳腺癌预后不良相关。然而，神经如何具体影响 TNBC 微环境，仍是一个谜。 2026 年 2 月 5 日， 复旦大学附属肿瘤医院 江一舟 教授、 邵志敏 教授及 倪金飞，复旦大学脑科学转化研究院 倪金飞 青年研究员等，在国际顶尖学术期刊 Cell 上发表了题为： Sensory neurons drive immune exclusion by stimulating a dense extracellular matrix ...

Core Viewpoint - The study reveals the dual role of intratumoral bacteria in regulating tumor immunity, highlighting the significant impact of bacterial invasion on immune responses and tumor recurrence [3][12][18]. Group 1: Tumor Microenvironment and Immune Response - Tumors are categorized as "hot" (immune-activated) or "cold" (immune-suppressive) based on immune cell infiltration and activity, with cold tumors showing insufficient immune response and resistance to immunotherapy [2]. - The presence of intratumoral bacteria is linked to regional immune-suppressive microenvironments, influencing cancer cell behavior and immune cell function through various mechanisms [2][3]. Group 2: Research Findings on Bacteria and Tumor Cells - The research conducted by Cai Shang's team demonstrates that intracellular bacteria activate the cGAS-STING-IL17B signaling pathway in cancer cells, leading to the induction of neutrophils into an immune-suppressive state, thus promoting tumor recurrence [3][12]. - In contrast, extracellular bacteria induce neutrophil subpopulations with anti-tumor functions, activating immune responses that inhibit tumor recurrence [3][12]. Group 3: Methodology and Experimental Models - A strict model for studying intracellular bacteria was established using organoid-bacteria co-culture systems, allowing for the specific investigation of the physiological functions of intracellular bacteria [8]. - In preclinical mouse models, the presence of intracellular bacteria was found to be a key factor in long-term tumor recurrence, with antibiotic treatment reducing recurrence rates significantly from 65% to 6.7% [9]. Group 4: Immune Cell Dynamics - Single-cell RNA sequencing revealed that intracellular bacteria induce neutrophils with myeloid-derived suppressor cell (G-MDSC) characteristics, while extracellular bacteria promote neutrophils with anti-tumor profiles [11][12]. - The cGAS-STING pathway is crucial for the immune reprogramming induced by bacterial invasion, with IL-17B identified as a key mediator in promoting immune suppression [12][14]. Group 5: Clinical Relevance and Future Directions - The study indicates that the strength of bacterial signals within tumor tissues correlates positively with neutrophil infiltration and is associated with poorer prognosis in breast cancer patients [15][19]. - Future research aims to explore targeted strategies for eliminating or limiting intracellular bacterial invasion, optimizing postoperative antibiotic and immunotherapy combinations to prevent tumor recurrence [19].

Core Viewpoint - The article discusses the complex interactions between cancer cells and the tumor microenvironment (TME), emphasizing the potential of targeted cancer immunotherapies to disrupt immunosuppressive interactions, although many therapies show limited durability due to a lack of understanding of these interactions [2][3]. Group 1: Research Findings - A study published by a team from the University of Chicago reveals that tumor-initiating stem cells (tSC) regulate the plasticity of neutrophils through metabolic reprogramming, creating a protective niche that allows them to survive cancer immunotherapy, leading to cancer recurrence [4]. - The research indicates that targeting the SOX2-FADS1-PGE2 signaling axis could serve as a novel combination therapy strategy to prevent immunotherapy resistance and tumor recurrence [4]. Group 2: Mechanisms of Immune Evasion - The study highlights the heterogeneity of tumor-associated neutrophils (TAN) and how different states of TAN arise and evolve, impacting the effectiveness of cancer immunotherapy [8]. - It was found that anti-PDL1 + CD40 agonist immunotherapy can induce TAN to regain anti-tumor activity in squamous cell carcinoma (SCC), while TAN at the tumor-stroma interface maintain their immunosuppressive state [8]. Group 3: Key Pathways and Implications - The SOX2 high-expressing tSCs enhance PGE2 signaling in TAN, which may disrupt interferon responses and inhibit the anti-tumor functions of TAN [9]. - Specific knockout of PGE2 receptors in neutrophils or using COX-2 inhibitors to block PGE2 synthesis can effectively restore the anti-tumor functions of neutrophils, enhancing the efficacy of immunotherapy and significantly reducing tumor recurrence rates [9]. Group 4: Overall Conclusions - The research explores how effective immunotherapies influence the plasticity of TAN, revealing how tSCs evade TAN-mediated anti-tumor immunity, allowing them to survive cancer immunotherapy and promote recurrence [12].

Core Viewpoint - The study highlights the role of Cathepsin-D (CTSD) in immune evasion in microsatellite stable colorectal cancer (MSS CRC), suggesting that targeting CTSD can enhance the efficacy of anti-PD-1 therapies [2][3][5]. Group 1: Research Findings - CTSD is overexpressed in colorectal cancer, leading to immune evasion and treatment resistance [7]. - CTSD promotes the degradation of MHC-I through the lysosomal pathway, which hinders its recycling to the cell surface [5][7]. - Gene knockout or pharmacological inhibition of CTSD can block immune evasion and enhance the efficacy of anti-PD-1 therapy [6][9]. Group 2: Implications for Treatment - Targeting CTSD in conjunction with anti-PD-1 immunotherapy could potentially improve treatment outcomes for patients with MSS CRC [8][9].

Core Viewpoint - The article discusses the challenges and advancements in immunotherapy for pancreatic ductal adenocarcinoma (PDAC), highlighting a recent phase 1/2 clinical trial that demonstrates the safety and feasibility of autologous multiantigen-targeted T cell therapy for PDAC patients [2][3]. Summary by Sections Immunotherapy Challenges - PDAC presents significant challenges for effective immunotherapy due to weak expression of target antigens and frequent upregulation of immunosuppressive molecules, leading to a "cold tumor" microenvironment [2]. - The heterogeneity of tumor antigen expression can result in rapid adaptation and modulation of target antigens, hindering the potential of T cell monotherapy [2]. Clinical Trial Overview - A phase 1/2 clinical trial named TACTOPS was conducted to evaluate the safety and feasibility of an autologous non-engineered T cell product administered monthly at a dose of 1×10^7 cells/m² [7]. - The trial included three arms: patients responsive to first-line chemotherapy (Group A, n=13), patients resistant to first-line chemotherapy (Group B, n=12), and patients with resectable disease (Group C, n=12) [7]. Trial Results - Among 56 participants, 37 received the infusion with only one treatment-related serious adverse event reported [8]. - Disease control rates were 84.6% for Group A and 25% for Group B, while 2 out of 9 patients in Group C remained disease-free after 66 months of follow-up [8]. - The infused cells persisted for 12 months post-treatment, with responders showing higher levels of tumor-directed T cells compared to non-responders [8]. Conclusion and Future Directions - The study confirms the feasibility of generating autologous multi-tumor-associated antigen (mTAA) T cells for patients at all stages of pancreatic cancer, with a maximum of six infusions at a dose of 1×10^7 cells/m² being safe [8]. - The clinical outcomes are associated with the peripheral expansion of mTAA-targeted T cell clones and the emergence of antigen spreading during treatment, suggesting further research into TAA T cells as a standalone therapy or in combination with other novel immunotherapies or standard treatments [8].

Core Viewpoint - The study identifies RNA-binding proteins (RBPs) as key regulators of immune evasion in high-grade serous ovarian cancer (C5-HGSC), suggesting that inhibiting IGF2BP1 can enhance the efficacy of PD-1 blockade therapy [2][4][6]. Group 1: Research Findings - The research integrates single-cell RNA sequencing with bulk RNA sequencing data, marking the first discovery that RBPs are critical for immune evasion in C5-HGSC [4]. - IGF2BP1 is confirmed as a core mediator of immune evasion in both in vitro and in vivo models, functioning by accelerating the degradation of IRF1 protein to block gamma-interferon signaling and inhibit MHC-I antigen presentation [4]. - The study reveals that IGF2BP1 dissociates the relationship between PD-L1 expression and IRF1-dependent transcription, thereby limiting immune cell infiltration and T cell activation [4]. Group 2: Therapeutic Implications - The small molecule compound BTYNB effectively inhibits IGF2BP1 and can work synergistically with PD-1 blockade to reverse immune evasion in vivo [4]. - The findings are validated using multispectral imaging technology in human HGSC tissue samples, highlighting the role of cancer embryonic RBPs as molecular drivers of the C5-HGSC subtype [4][6].

Core Insights - The recent increase in COVID-19 positivity rates indicates a small peak, with notable cases leading to event cancellations, such as singer Eason Chan's concert postponement [1][2] Summary by Sections Current COVID-19 Situation - The positivity rate for COVID-19 has risen from 7.5% to 16.2% in outpatient flu-like cases and from 3.3% to 6.3% in hospitalized severe acute respiratory infection cases during the monitoring period from March 31 to May 4 [2] - Experts warn that the current wave is a small peak, with predictions that the positivity rate will decline to 8%-10% by early June and below 5% by mid to late June [5] Vulnerable Populations - Elderly individuals remain a high-risk group, with the highest positivity rates observed in those aged 60 and above during the recent monitoring period [3] - Immunocompromised individuals and those with chronic conditions are particularly at risk for severe outcomes [3][4] Virus Characteristics - The current circulating strain is primarily the NB.1 series, which shows no significant change in pathogenicity compared to previous strains, although it has a higher transmission advantage [6] - The NB.1 strain exhibits greater immune evasion capabilities but is not expected to cause more severe disease than previous variants [6] Regional Variations - Southern provinces have reported slightly higher COVID-19 positivity rates compared to northern provinces, attributed to climatic differences that favor virus transmission [7]