Core Viewpoint - Immune checkpoint blockade (ICB) therapy has shown promise in improving clinical outcomes for some head and neck squamous cell carcinoma (HNSCC) patients, but the mechanisms regulating treatment response remain poorly understood [3][6]. Group 1: Role of Gut Microbiome - Increasing research emphasizes the significant role of the gut microbiome in determining the effectiveness of immunotherapy, with specific gut bacteria shown to enhance anti-tumor immunity and T cell proliferation in cancer patients [3]. - Intratumoral bacteria have been identified as immunosuppressive and promote resistance to ICB therapy in HNSCC [4]. Group 2: Research Findings - A study analyzing samples from the CIAO clinical trial found that only the total abundance of intratumoral bacteria could predict patient response to ICB therapy, a conclusion validated across multiple independent cohorts [6]. - High abundance of intratumoral bacteria correlates with an immunosuppressive tumor microenvironment characterized by neutrophil accumulation and reduced T cells and other adaptive immune cells [6]. - Experimental manipulation of intratumoral bacterial abundance in a mouse model of HNSCC replicated the immunological associations observed in clinical trial participants [6]. Group 3: Implications for Immunotherapy - The findings indicate that high levels of intratumoral bacteria are a key inhibitory factor for anti-tumor immunity and contribute to resistance against immunotherapy [7].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 抗 PD-1/PD-L1 免疫检查点阻断疗法，在多种癌症类型中展示了强大的治疗效果。然而，耐药性始终是制约其临床疗效的关键挑战。迄今为止，研究人员所揭示 的耐药机制主要涉及 PD-L1 之外的外部因素。 2026 年 1 月 2 日，陆军军医大学第一附属医院（西南医院） 仰毅 研究员、 卞修武 院士、 齐晓伟 教授等，在 Cell Research 期刊发表了题为： Tumor PD- L1 induces β2m ubiquitylation and degradation for cancer cell immune evasion 的研究论文。 该研究表明 ， 肿瘤 PD-L1 诱导 β2m 泛素化和降解，从而实现癌细胞免疫逃逸 。这一发现 揭示了 PD-L1 在肿瘤细胞免疫逃逸中一个前所未有的新功能，拓展 了对免疫检查点阻断 （ICB） 疗法的内在耐药机制的认识。 PD-L1 介导的 β2m 泛素化在肿瘤免疫逃逸中的作用 β2-微球蛋白 （ β2-microglobulin， β2m） 是 主要组织相容性复合物 I 类 （MHC-I） 分子 的轻链，对于肿瘤细胞 ...

Core Viewpoint - Ferroptosis is emerging as a promising anti-tumor therapy driven by the oxidation of polyunsaturated fatty acids in cell membranes, leading to lipid peroxidation and cell death, while also releasing damage-associated molecular patterns (DAMPs) that enhance T cell activation [1][4]. Summary by Sections Ferroptosis Mechanism and Challenges - Ferroptosis induces cell death through increased intracellular iron, reduced glutathione synthesis, and elevated reactive oxygen species (ROS) levels. However, the upregulation of PD-L1 in tumor cells can inhibit cytotoxic T cell recognition, leading to immune suppression [1][5]. Research Development - A team from Shenyang Pharmaceutical University and Shenzhen University developed a fluorinated prodrug-engineered nano-remodeler that combines a PD-L1 inhibitor (JQ1) and a ferroptosis inducer (sorafenib) to enhance oxygen supply in hypoxic tumors, significantly improving the efficacy of ferroptosis and anti-tumor immunogenicity [2][6]. Nano-remodeler Characteristics - The engineered nano-remodeler (FJSO NA) has high oxygen solubility and releases oxygen in low-pressure environments, alleviating hypoxia in solid tumors, downregulating PD-L1 expression, and enhancing ferroptosis induction and anti-tumor immune responses [6][8]. Efficacy and Safety - The study demonstrated that the nano-remodeler effectively inhibited tumor growth in various models without significant toxicity, indicating a promising direction for enhancing ferroptosis-based immunotherapy by addressing the hypoxic tumor microenvironment [8].

Core Viewpoint - The article discusses the potential of SARS-CoV-2 mRNA vaccines as broad-spectrum immune activators that can sensitize tumors to immune checkpoint inhibitors (ICIs), significantly improving survival rates in advanced cancer patients [4][10]. Group 1: Impact of mRNA Vaccines on Cancer Treatment - Recent studies indicate that systemic administration of high-immunogenic mRNA nanoparticles can reset the immune microenvironment, making resistant tumors sensitive to ICIs [2]. - The research from MD Anderson Cancer Center shows that advanced cancer patients who received the SARS-CoV-2 mRNA vaccine within 100 days before starting ICI treatment had significantly extended overall survival [8]. - Specifically, the median survival for non-small cell lung cancer patients increased from 20.6 months to 37.3 months, and for metastatic melanoma patients, it rose from 26.7 months to over 36 months [8]. Group 2: Mechanism of Action - The study found that the SARS-CoV-2 mRNA vaccine significantly increased type I interferon (IFN-I) levels and activated antigen-presenting cells, which in turn stimulated CD8+ T cells to combat tumors [10][12]. - The vaccine also enhanced PD-L1 protein expression in tumors and promoted T lymphocyte activation within the tumor microenvironment [10]. Group 3: Clinical Implications - The findings suggest that clinically available mRNA vaccines targeting non-tumor-associated antigens can serve as powerful immune modulators, making tumors sensitive to ICIs [12]. - The combination of SARS-CoV-2 mRNA vaccines with ICIs can maintain T cell responses, thereby inhibiting tumor growth and improving cancer patient survival rates [12].

Core Viewpoint - The article discusses the potential of a newly identified gut bacterium, YB328, in enhancing the efficacy of immune checkpoint blockade (ICB) therapies, particularly in cancer treatment, by promoting dendritic cell maturation and CD8+ T cell activation [1][4][7]. Group 1: Research Findings - A study published in Nature identified a gut bacterium that accelerates dendritic cell maturation and migration, increasing the response of CD8+ T cells to various tumor antigens, thereby enhancing anti-tumor immunity [2]. - The research analyzed fecal samples from 50 cancer patients undergoing PD-1 blockade therapy, revealing that the YB328 strain was significantly enriched in patients who responded to the treatment [4]. - In mouse models, fecal transplants from non-responding patients supplemented with YB328 showed significantly improved anti-tumor effects of PD-1 blockade therapy, indicating YB328's potential role in enhancing cancer immunotherapy [4]. Group 2: Mechanism of Action - YB328 promotes the differentiation of CD103+ CD11b- conventional dendritic cells (cDC), which are crucial for cross-presenting antigens to CD8+ T cells [5]. - The bacterium stimulates various Toll-like receptors (TLRs), leading to the phosphorylation of S6K and STAT3, and induces the expression of IRF8, facilitating cDC differentiation [5]. - The activated cDC migrate to tumor-draining lymph nodes and the tumor microenvironment, where they activate CD8+ T cells and induce PD-1+ CD8+ T cells targeting multiple tumor antigens [5][7]. Group 3: Future Directions - The research team is collaborating with a biotechnology company to conduct human clinical trials within the next three years to test whether YB328 can improve cancer patients' responses to checkpoint inhibitors [8].

Core Viewpoint - Immune checkpoint inhibitors (ICIs) have transformed the treatment of various solid tumors, but resistance remains a significant challenge, particularly in advanced and recurrent ovarian cancer, where response rates to single-agent PD-1/PD-L1 inhibitors are only 5%-15% [2][3] Group 1: Research Findings - A study published in Nature by a team from MD Anderson Cancer Center found that patients with PPP2R1A gene mutations had significantly improved survival after receiving combined anti-PD-1/PD-L1 and anti-CTLA-4 immunotherapy compared to those with wild-type PPP2R1A [3][6] - The presence of PPP2R1A mutations enhances tumor response to immunotherapy, and this finding was validated across various cancer types in clinical cohorts [3][9] - In recurrent ovarian cancer, dual targeting of PD-1/PD-L1 and CTLA-4 showed a response rate of 31.4% compared to 12.2% for single-agent PD-1 therapy, indicating a potential benefit for patients with ovarian clear cell carcinoma (OCCC) [5][6] Group 2: Clinical Implications - The study suggests that targeting PPP2R1A could represent an effective strategy to improve outcomes for cancer patients undergoing immunotherapy [9] - Enhanced immune cell infiltration and signaling pathways were observed in tumors with PPP2R1A mutations, indicating a more favorable immune environment for treatment [8] - The research team is conducting prospective trials to explore the efficacy of dual immune checkpoint blockade in OCCC patients, particularly those with platinum-resistant disease [5][6]

Core Viewpoint - The study highlights the role of metabolic reprogramming in promoting immune suppression in hepatocellular carcinoma (HCC), which is crucial for developing targeted and effective anti-tumor strategies [2][3]. Group 1: Research Findings - The research integrates multi-omics data, including metabolomics, transcriptomics, and single-cell sequencing, to elucidate how tumor cells produce and actively export N1-acetylspermidine (N1-Ac-Spd), leading to immune suppression [3][4]. - N1-Ac-Spd accumulates in HCC tissues and increases in paired plasma compared to non-tumor liver tissues, promoting tumor progression and weakening the efficacy of immune checkpoint blockade (ICB) therapy in preclinical models [4][6]. - Inflammatory macrophages enhance the expression of SAT1 in HCC cells, which increases the export of N1-Ac-Spd through the polyamine transporter SLC3A2, creating an immunosuppressive tumor microenvironment [5][6]. Group 2: Mechanistic Insights - N1-Ac-Spd activates SRC signaling in a charge-dependent manner, leading to the polarization of CCL1+ macrophages and recruitment of regulatory T cells, which diminishes the effectiveness of ICB therapy [5][6]. - Blocking the synthesis of N1-Ac-Spd or targeting SLC3A2, SAT1, or CCL1 can significantly enhance the anti-tumor effects of ICB therapy [5][6]. Group 3: Implications for Treatment - The findings reveal mechanisms by which metabolic reprogramming fosters an immunosuppressive tumor microenvironment, providing theoretical foundations and potential intervention targets for enhancing HCC treatment [6][9].

Core Viewpoint - The study highlights that intravesical administration of Bacillus Calmette-Guérin (BCG) vaccine can reprogram hematopoietic stem/progenitor cells (HSPC) to enhance anti-tumor immunity, indicating its potential in cancer immunotherapy [1][2][4][6]. Group 1: Mechanism of Action - BCG vaccine can colonize the bone marrow and reprogram HSPC, enhancing myeloid hematopoiesis in both mice and humans [3][4]. - The reprogrammed HSPC can generate neutrophils, monocytes, and dendritic cells, which reshape the tumor microenvironment and drive T cell-dependent anti-tumor responses [3][4]. Group 2: Key Findings - The study confirms that intravesical BCG administration leads to systemic reprogramming of HSPC [4]. - The reprogramming of HSPC is dependent on INFγ and enhances the antigen-presenting function of myeloid cells [4]. - Reprogrammed myeloid cells increase T cell infiltration and work synergistically with PD-1 blockade for anti-cancer effects [4][6]. Group 3: Implications - The findings underscore the broad potential of HSPC reprogramming in enhancing T cell-dependent tumor immunity, suggesting a novel approach in cancer treatment [6].