Core Viewpoint - Neoadjuvant immune checkpoint blockade (NICB) therapy has become a first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC), significantly improving progression-free survival for patients. However, the pathological complete response (pCR) rate is ≤40%, indicating a need to elucidate the mechanisms of resistance to NICB to optimize treatment outcomes [3][7]. Group 1 - A recent study identified a subset of senescent EGR1+ B cells associated with poor pathological responses in ESCC patients undergoing NICB therapy, highlighting the role of these cells in treatment failure [8][11]. - EGR1 is a key transcription factor regulating B cell senescence, and the presence of EGR1+ B cells serves as a predictive marker for poor prognosis across multiple cohorts [8][11]. - The senescent B cells drive chronic inflammation in the tumor microenvironment (TME) through a senescence-associated secretory phenotype (SASP), which induces immunosuppressive TREM2+ tumor-associated macrophages (TAMs), ultimately inhibiting anti-tumor immune responses [8][11]. Group 2 - Fisetin, a natural flavonoid found in various fruits and vegetables, has been shown to alleviate B cell senescence and enhance the efficacy of NICB therapy [10][14]. - The study emphasizes that targeting B cell senescence could be a viable strategy to improve the effectiveness of NICB in treating ESCC [14].

Core Viewpoint - The study reveals a signaling axis involving visceral adipose tissue-derived extracellular vesicles (VAT-EV) that promotes pancreatic cancer development and resistance to immune checkpoint blockade therapy in obese patients, suggesting potential new therapeutic strategies for obesity-related cancers [4][7]. Group 1: Research Findings - The research identifies that VAT-EV from obese patients facilitates communication with pancreatic ductal adenocarcinoma (PDAC) tissues [4]. - PDAC cells can internalize VAT-EV, leading to the stabilization of ribonuclease Rnaset2b and the production of free pseudouridine [4][5]. - Pseudouridine activates mast cells by increasing reactive oxygen species (ROS) and reducing H3K27me3 modifications, creating an immunosuppressive tumor microenvironment that promotes cancer progression [4][5]. Group 2: Implications for Therapy - Targeting the VAT-EV-CTSA-pseudouridine-mast cell signaling pathway could enhance the efficacy of immune checkpoint blockade therapy for PDAC [5][7]. - The study provides hope for developing new treatment strategies for obesity-related cancers by elucidating the molecular mechanisms linking obesity and cancer [7].

Core Viewpoint - The article discusses the relationship between aging and the immune system, emphasizing how immune responses change with age and the potential for manipulating immune function to extend healthy lifespan [2][24]. Group 1: Aging and Immune Response - Aging leads to significant changes in immune cell function, including a bias towards myeloid output from bone marrow, accumulation of senescent T cells, and increased levels of systemic inflammatory cytokines [6][24]. - The immune system is increasingly recognized as a key regulator of systemic aging, potentially driving the aging process rather than merely responding to it [24]. Group 2: Mitochondrial Function and Immune Aging - Mitochondrial dysfunction is central to immune aging, as age-related decline in mitochondrial function weakens immune responses and promotes chronic inflammation [7][8]. - Mitochondria also play a role in systemic signaling, influencing immune responses across different tissues, which is often overlooked in current models of immune aging [7][8]. Group 3: Spaceflight as a Model for Aging - Research using spaceflight environments reveals that many immune changes observed in aging, such as increased inflammatory mediators and impaired adaptive immune responses, can also occur in microgravity [9][12]. - This suggests that spaceflight can serve as a valuable model for studying the mechanisms of immune aging [9][12]. Group 4: Vaccine Response in the Elderly - Elderly individuals typically exhibit lower antibody titers and fewer memory B cells post-vaccination, leading to impaired protective immune responses [14]. - Recent findings indicate that the germinal center response in older adults can be enhanced, paving the way for improved vaccine strategies tailored to aging populations [14]. Group 5: T Cell Changes with Age - Aging is associated with various changes in T cells, including reduced diversity in T cell receptor repertoires and a shift towards inflammatory phenotypes [15][16]. - Understanding whether these changes are adaptive or degenerative is crucial for developing therapeutic strategies targeting age-related immune dysfunction [15][16]. Group 6: Personalized Immunotherapy - The potential of immune modulation in treating diseases is significant, with a focus on how aging affects the efficacy of immunotherapies like CAR-T cell therapy [19]. - Tailoring immunotherapy strategies based on age-related changes in immune cell function could enhance treatment outcomes across different age groups [19]. Group 7: Future Directions in Aging Research - The field must transition from defining aging processes to developing interventions, including identifying biomarkers and strategies to selectively target pathological aging cells [21]. - Integrating artificial intelligence with systems immunology could provide new insights into the regulatory nodes of immune aging, potentially allowing for interventions that recalibrate immune responses to slow aging [24][21].

Core Viewpoint - The research highlights the role of dietary flavonoid quercetin and its microbial metabolite DOPAC in enhancing CD8⁺ T cell anti-tumor immunity, suggesting DOPAC as a potential candidate for cancer immunotherapy [2][8]. Group 1: Mechanism of Action - Quercetin, when metabolized by gut microbiota, produces DOPAC, which enhances CD8⁺ T cell anti-tumor immunity through NRF2-mediated mitophagy [3][4]. - DOPAC binds directly to KEAP1 protein, disrupting its interaction with NRF2, thereby preventing KEAP1-mediated NRF2 degradation [4]. - Increased NRF2 activity leads to enhanced transcription of BNIP3, promoting mitophagy and improving the adaptability of CD8⁺ T cells in the tumor microenvironment [4][6]. Group 2: Synergistic Effects - DOPAC exhibits a synergistic effect with immune checkpoint blockade (ICB) therapy, further inhibiting tumor growth [5][6]. Group 3: Implications for Cancer Treatment - The findings underscore the importance of dietary nutrients and their microbial metabolites in regulating anti-tumor immune responses, positioning DOPAC as a promising candidate for cancer immunotherapy [8].

Core Viewpoint - The study reveals the critical role of immature neutrophils in the bone metastatic microenvironment and suggests a potential therapeutic strategy to improve cancer immunotherapy by regulating these cells [3][7]. Group 1: Research Findings - Immature neutrophils dominate the bone metastatic microenvironment in both mouse models and cancer patients [5]. - DKK1 induces neutrophils to exhibit an immature functional state, which possesses strong immunosuppressive capabilities, inhibiting CD8+ T cell anti-tumor responses [5]. - The DKK1-CKAP4-STAT6 signaling pathway drives CHI3L3 expression, essential for the immunosuppressive role of immature neutrophils in bone metastases [5]. Group 2: Therapeutic Implications - Blocking DKK1 can promote neutrophil maturation, improve the immune microenvironment, induce tumor shrinkage, and enhance responses to immune checkpoint blockade therapy [3][5]. - The findings propose a promising new strategy for combined immunotherapy targeting bone metastases by modulating neutrophil activity [7].