Volume 13, Issue 1

In the evolving landscape of cancer treatment, the strategic manipulation of regulated cell death (RCD) pathways has emerged as a crucial component of effective anti-tumor immunity. Evidence suggests that tumor cells undergoing RCD can modify the immunogenicity of the tumor microenvironment (TME), potentially enhancing its ability to suppress cancer progression and metastasis. In this review, we first explore the mechanisms of apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis, along with the crosstalk between these cell death modalities. We then discuss how these processes activate antigen-presenting cells, facilitate the cross-priming of CD8+ T cells, and trigger anti-tumor immune responses, highlighting the complex effects of novel forms of tumor cell death on TME and tumor biology. Furthermore, we summarize potential drugs and nanoparticles that can induce or inhibit these emerging RCD pathways and their therapeutic roles in cancer treatment. Finally, we put forward existing challenges and future prospects for targeting RCD in anti-cancer immunity. Overall, this review enhances our understanding of the molecular mechanisms and biological impacts of RCD-based therapies, providing new perspectives and strategies for cancer treatment.

Aging and age-related diseases are major drivers of multimorbidity and mortality worldwide. Cellular senescence is a hallmark of aging. The accumulation of senescent cells is causally associated with pathogenesis of various age-associated disorders. Due to their promise for alleviating age-related disorders and extending healthspan, therapeutic strategies targeting senescent cells (senotherapies) as a means to combat aging have received much attention over the past decade. Among the conventionally used approaches, one is the usage of small-molecule compounds to specifically exhibit cytotoxicity toward senescent cells or inhibit deleterious effects of the senescence-associated secretory phenotype (SASP). Alternatively, there are immunotherapies directed at surface antigens specifically upregulated in senescent cells (seno-antigens), including chimeric antigen receptor (CAR) therapies and senolytic vaccines. This review gives an update of the current status in the discovery and development of senolytic therapies, and their translational progress from preclinical to clinical trials. We highlight the current challenges faced by senotherapeutic development in the context of senescence heterogeneity, with the aim of offering novel perspectives for future anti-aging interventions aimed at enhancing healthy longevity.

Background and Objectives Recently, a series of publications discuss what kind of clinical and technical information is important to know before performing endoscopic ultrasound (EUS) examinations. This paper aims to investigate variations in the performance of EUS examinations in different countries worldwide to present views and experiences on the use of pre-EUS investigations. Methods In a multinational and multidisciplinary survey, more than 100 practicing EUS endoscopists were surveyed by a questionnaire asking for their level of education and training, their experience in diagnostic and therapeutic procedures, preferred technical use and procedural steps before EUS examination. Substantial geographic variation not only in the level of training and mandatory imaging prior to EUS, but consequently also in the standards and practice of EUS examinations and advanced EUS guided therapeutic procedures were observed. The participants’ preferences regarding technical use and procedural steps prior to EUS examinations were assessed according to their level of education and training experience. Results Transabdominal ultrasound (TUS) is performed prior to EUS by the EUS endoscopists themselves in most European countries but not in North and South Americas where non-invasive pre-EUS imaging is delegated to other specialties such as radiology. Different training backgrounds, cultural beliefs, infrastructures, available equipment and access to training programs have a strong impact on the EUS workforce and EUS procedural practice across the continents. Conclusions The study results suggest existence of relevant geographical differences that reflect not only the different levels of education in different settings but also differences regarding technical standards for the performance of EUS and TUS examinations worldwide.

Background and Objectives This study aimed to elucidate the role of the glymphatic system—a crucial pathway for clearing waste in the brain—in the aging process and its contribution to cognitive decline. We specifically focused on the diffusion tensor imaging analysis along the perivascular space (ALPS) index as a noninvasive biomarker of glymphatic function. Methods Data were drawn from the Alzheimers Disease Neuroimaging Initiative (ADNI) database and a separate validation cohort to analyze the ALPS index in cognitively normal older adults. The relationships among the ALPS index, brain morphometry, and memory performance were examined. Results As a biomarker of glymphatic function, the ALPS index appeared to decline with age in both cohorts. According to the brain morphology analysis, the ALPS index was positively correlated with the thickness of the left entorhinal cortex ( r = 0.258, P false discovery rate (FDR) = 2.96 × 10 -4 ), and it played a mediating role between aging and left entorhinal cortex thinning. The independent cohort further validated the correlation between the ALPS index and the left entorhinal cortex thickness ( r = 0.414, P FDR = 0.042). Additionally, in both the primary and validation cohorts, the ALPS index played a significant mediating role in the relationship between age and durable or delayed memory decline. Conclusion This study highlights the ALPS index as a promising biomarker for glymphatic function and links it to atrophy of the core memory brain regions during aging. Furthermore, these results suggest that targeting glymphatic dysfunction could represent a novel therapeutic approach to mitigate age-related memory decline. Graphical Abstract

Background and Objectives Nidogen 1 (NID1) is a highly conserved structural component of the extracellular matrix (ECM), which interacts with different basement membrane (BM) proteins to form a stabilized meshwork. The promoting ability of NID1 in cancer development and metastasis has been demonstrated in multiple cancer types, including ovarian cancer, breast cancer, and hepatocellular carcinoma (HCC). This suggests that NID1 holds great potential as a therapeutic target for cancer treatment. However, currently, there is a lack of commercially available neutralizing antibody for clinical testing and treatment. Methods To address this, we utilized hybridoma technology to develop a monoclonal neutralizing antibody which targets the critical G2 region of NID1. The therapeutic effect of this NID1 neutralizing antibody against a wide range of human cancer cells was evaluated. Results The results showed that NID1 neutralizing antibody effectively attenuated the growth, motility and metastasis of HCC, lung cancer, breast cancer and nasopharyngeal carcinoma cells in vitro . The proof-of-concept of targeting NID1 using neutralizing antibody was further demonstrated in various animal models. Mechanistically, our findings indicate that treatment with NID1 neutralizing antibody leads to the deregulation of hypoxia-inducible factor-1 (HIF-1α) pathway in cancer cells. Conclusions Taken together, this study offers promising prospects for a new pan-cancer monoclonal antibody-based strategy by targeting the tumor-associated membrane protein NID1.