Fungal microbes are a small but immunoreactive component of the human microbiome, which may influence cancer development, progression and therapeutic response. Immunosenescence is a process of immune dysfunction that occurs with aging, including lymphoid organ remodeling, contributing to alterations in the immune system in the elderly, which plays a critical role in many aspects of cancer. There is evidence for the interactions between fungi and immunosenescence in potentially regulating cancer progression and remodeling the tumor microenvironment (TME). In this review, we summarize potential roles of commensal and pathogenic fungi in modulating cancer-associated processes and provide more-detailed discussions on the mechanisms of which fungi affect tumor biology, including local and distant regulation of the TME, modulating antitumor immune responses and interactions with neighboring bacterial commensals. We also delineate the features of immunosenescence and its influence on cancer development and treatment, and highlight the interactions between fungi and immunosenescence in cancer. We discuss the prospects and challenges for harnessing fungi and immunosenescence in cancer diagnosis and/or treatment. Considering the limited understanding and techniques in conducting such research, we also provide our view on how to overcome challenges faced by the exploration of fungi, immunosenescence and their interactions on tumor biology.

Non-small cell lung cancer (NSCLC), the most prevalent form of lung cancer, remains a leading cause of cancer-related mortality worldwide, particularly among elderly individuals. The phenomenon of immunosenescence, characterized by the progressive decline in immune cell functionality with aging, plays a pivotal role in NSCLC progression and contributes to the diminished efficacy of therapeutic interventions in older patients. Immunosenescence manifests through impaired immune surveillance, reduced cytotoxic responses, and increased chronic inflammation, collectively fostering a pro-tumorigenic microenvironment. This review provides a comprehensive analysis of the molecular, cellular, and genetic mechanisms of immunosenescence and its impact on immune surveillance and the tumor microenvironment (TME) in NSCLC. We explore how aging affects various immune cells, including T cells, B cells, NK cells, and macrophages, and how these changes compromise the immune system's ability to detect and eliminate tumor cells. Furthermore, we address the challenges posed by immunosenescence to current therapeutic strategies, particularly immunotherapy, which faces significant hurdles in elderly patients due to immune dysfunction. The review highlights emerging technologies, such as single-cell sequencing and CRISPR-Cas9, which offer new insights into immunosenescence and its potential as a therapeutic target. Finally, we outline future research directions, including strategies for rejuvenating the aging immune system and optimizing immunotherapy for older NSCLC patients, with the goal of improving treatment efficacy and survival outcomes. These efforts hold promise for the development of more effective, personalized therapies for elderly patients with NSCLC.

Senescence is an inherent cellular mechanism triggered as a response to stressful insults. It associates with several aspects of cancer progression and therapy. Senescent cells constitute a highly heterogeneous cellular population and their identification can be very challenging. In fact, the term "senescence" has been often misused. This is also true in the case of immune cells. While several studies indicate the presence of senescent-like features (mainly in T cells), senescent immune cells are poorly described. Under this prism, we herein review the current literature on what has been characterized as T cell senescence and provide insights on how to accurately discriminate senescent cells against exhausted or anergic ones. We also summarize the major metabolic and epigenetic modifications associated with T cell senescence and underline the role of senescent T cells in the tumor microenvironment (TME). Moreover, we discuss how these cells associate with standard clinical therapeutic interventions and how they impact their efficacy. Finally, we underline the importance of precise identification and thorough characterization of "truly" senescent T cells in order to design successful therapeutic manipulations that would delay cancer incidence and maximize efficacy of immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by late detection and poor prognosis. Recent research highlights the pivotal role of epigenetic alter- ations in driving PDAC development and progression. These changes, in conjunction with genetic mutations, contribute to the intricate molecular landscape of the disease. Specific modifications in DNA methylation, histone marks, and non-coding RNAs are emerging as robust predictors of disease progression and patient survival, offering the potential for more precise prognostic tools compared to conventional clinical staging. Moreover, the detection of epigenetic alterations in blood and other non-invasive samples holds promise for earlier diagnosis and improved manage- ment of PDAC. This review comprehensively summarises current epigenetic research in PDAC and identifies persisting challenges. These include the complex nature of epigenetic profiles, tumour hetero- geneity, limited access to early-stage samples, and the need for highly sensitive liquid biopsy technologies. Addressing these challenges requires the standardisation of methodologies, integra- tion of multi-omics data, and leveraging advanced computational tools such as machine learning and artificial intelligence. While resource-intensive, these efforts are essential for unravelling the functional consequences of epigenetic changes and translating this knowledge into clinical appli- cations. By overcoming these hurdles, epigenetic research has the potential to revolutionise the management of PDAC and improve patient outcomes.

Cellular senescence is a response to various stress signals, which is characterized by stable cell cycle arrest, alterations in cellular morphology, metabolic reprogramming and production of senescence-associated secretory phenotype (SASP). When it occurs in the immune system, it is called immunosenescence. Cervical cancer is a common gynecological malignancy, and cervical cancer screening is generally recommended before the age of 65. Elderly women (≥65 years) are more often diagnosed with advanced disease and have poorer prognosis compared to younger patients. Despite extensive research, the tumor microenvironment requires more in-depth exploration, particularly in elderly patients. In cervical cancer, senescent cells have a double-edged sword effect on tumor progression. Induction of preneoplastic cell senescence prevents tumor initiation, and several treatment approaches of cervical cancer act in part by inducing cancer cell senescence. However, senescent immune cell populations within the tumor microenvironment facilitate tumor development, recurrence, treatment resistance, etc. Amplification of beneficial effects and inhibition of aging-related pro-tumorigenic pathways contribute to improving antitumor effects. This review discusses senescent cancer and immune cells present in the tumor microenvironment of cervical cancer and how these senescent cells and their SASP remodel the tumor microenvironment, influence antitumor immunity and tumor initiation and development. Moreover, we discuss the significance of senotherapeutics that enable to eliminate senescent cells and prevent tumor progression and development through improving antitumor immunity and affecting the tumor microenvironment.

Elevated lipid metabolism is one of hallmarks of malignant tumors. Lipids not only serve as essential structural components of biological membranes but also provide energy and substrates for the proliferation of cancer cells and tumor growth. Cancer cells meet their lipid needs by coordinating the processes of lipid absorption, synthesis, transport, storage, and catabolism. As research in this area continues to deepen, numerous new discoveries have emerged, making it crucial for scientists to stay informed about the developments of cancer lipid metabolism. In this review, we first discuss relevant concepts and theories or assumptions that help us understand the lipid metabolism and -based cancer therapies. We then systematically summarize the latest advancements in lipid metabolism including new mechanisms, novel targets, and up-to-date pre-clinical and clinical investigations of anti-cancer treatment with lipid metabolism targeted drugs. Finally, we emphasize emerging research directions and therapeutic strategies, and discuss future prospective and emerging challenges. This review aims to provide the latest insights and guidance for research in the field of cancer lipid metabolism.

Doxorubicin (DOX) is an anthracycline antitumor drug discovered in 1969, which can care for leukemia, breast cancer, lymphoma, and sarcoma. However, cardiotoxicity induced by DOX seriously limits its clinical value. The etiopathogenesis and therapeutic strategies are not unified. Autophagy is a critical mechanism in the progression of DOX-induced cardiotoxicity (DIC), autophagy intervention is a potential therapeutic strategy for DIC. Natural product has been considered as a complementary and alternative approach to treat cardiovascular disease. In this review, we summarize the pathology of autophagy in DIC and the natural products for DIC therapy.

With the rapid development of immunological techniques in recent years, our understanding of immune senescence has gradually deepened, but the role of immune senescence in cancer biology remains incompletely elucidated. Understanding these mechanisms and interactions is crucial for the development of tumor biology. This review examines five key areas: the classification and main features of immune senescence, factors influencing immune cell senescence in cancer, the reciprocal causal cycle between immune senescence and malignancy, and the potential of immune senescence as a target for cancer immunotherapy.

Cellular senescence is a state of permanent proliferative arrest that occurs in response to DNA damage-inducing endogenous and exogenous stresses, and is often accompanied by dynamic molecular changes such as a senescence-associated secretory phenotype (SASP). Accumulating evidence indicates that age-associated increases in the upstream and downstream signals of regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, are closely related to the induction of cellular senescence and its phenotype. Furthermore, elevated levels of pro-inflammatory SASP factors with aging can be both a cause and consequence of several cell death modes, suggesting the reciprocal effects of cellular senescence and cells undergoing regulated cell death. Here, we review the critical molecular pathways of the regulated cell death forms and describe the crosstalk between aging-related signals and cancer. In addition, we discuss how targeting regulated cell death could be harnessed in therapeutic interventions for cancer. ABBREVIATIONS: Abbreviations that are not standard in this field are defined at their first occurrence in the article and are used consistently throughout the article.

The Retinoblastoma (RB) protein is crucial for regulating gene transcription and chromatin remodeling, impacting cell cycle progression, cellular senescence, and tumorigenesis. Cellular senescence, characterized by irreversible growth arrest and phenotypic alterations, serves as a vital barrier against tumor progression and age-related diseases. RB is crucial in mediating senescence and tumor suppression by modulating the RB-E2F pathway and cross talking with other key senescence effectors such as p53 and p16. The interplay between RB-mediated cell cycle arrest and cellular senescence offers critical insights into tumorigenesis and potential therapeutic strategies. Leveraging RB-mediated senescence presents promising opportunities for cancer therapy, including novel approaches in tumor immunotherapy designed to enhance treatment efficacy. This review highlights recent advancements in the RB signaling pathway, focusing on its roles in cellular senescence and tumor suppression, and discusses its potential to improve tumor management and clinical outcomes.

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of all common solid cancers. For the large majority of PDAC patients, only systemic therapies with very limited efficacy are indicated. In addition, immunotherapies have not brought the advances seen in other cancer types. Several key characteristics of PDAC contribute to poor treatment outcomes, and in this review, we will discuss how these characteristics are best captured in currently available ex vivo or in vitro model systems. For instance, PDAC is hallmarked by a highly desmoplastic and immune-suppressed tumor microenvironment that impacts disease progression and therapy resistance. Also, large differences in tumor biology exist between and within tumors, complicating treatment decisions. Furthermore, PDAC has a very high propensity for locally invasive and metastatic growth. The use of animal models is often not desirable or feasible and several in vitro and ex vivo model systems have been developed, such as organotypic cocultures and tissue slices, among others. However, the absence of a full host organism impacts the ability of these models to accurately capture the characteristics that contribute to poor outcomes in PDAC. We will discuss the caveats and advantages of these model systems in the context of PDAC's key characteristics and provide recommendations on model choice and the possibilities for optimization. These considerations should be of use to researchers aiming to study PDAC in the in vitro setting.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal and common form of pancreatic cancer, it has no specific symptoms, and most of the patients are diagnosed when the disease is already at an advanced stage. Chemotherapy typically has only a modest effect, making surgery the most effective treatment option. However, only a small percentage of patients are amenable to surgery. One viable strategy to reduce PDAC death burden associated with the disease is to focus on precursor lesions and identify markers able to predict who will evolve into PDAC. While most PDACs are believed to be preceded by pancreatic intraepithelial neoplasms (PanINs), 5-10 % arise from Intraductal papillary mucinous neoplasms (IPMNs), which are mass-forming cystic lesions that are very common in the general population. IPMNs offer an invaluable model of pancreatic carcinogenesis for researchers to analyse, as well as a target population for PDAC early detection by clinicians. The evolution of IPMN into cancer is a complex and multistep process, therefore the identification of individual markers will not be the solution. In recent years, multiple omics technologies have been instrumental to identify possible biomarkers of IPMN progression and carcinogenesis. The only foreseeable strategy will be to integrate multi-omics data, alongside clinical and morphological features, into a progression score or signature using either standard epidemiologic tools or artificial intelligence. The aim of this manuscript is to review the current knowledge on genetic biomarkers and to briefly mention also additional omics, such as metabolomics, the exposome, the miRNome and epigenomics of IPMNs.

Damage-associated molecular patterns (DAMPs) are endogenous molecules released by cells in response to injury or stress, recognized by host pattern recognition receptors that assess the immunological significance of cellular damage. The interaction between DAMPs and innate immune receptors triggers sterile inflammation, which serves a dual purpose: promoting tissue repair and contributing to pathological conditions, including age-related diseases. Chronic inflammation mediated by DAMPs accelerates immunosenescence and influences both tumor progression and anti-tumor immunity, underscoring the critical role of DAMPs in the nexus between aging and cancer. This review explores the characteristics of immunosenescence and its impact on age-related cancers, investigates the various types of DAMPs, their release mechanisms during cell death, and the immune activation pathways they initiate. Additionally, we examine the therapeutic potential of targeting DAMPs in age-related diseases. A detailed understanding of DAMP-induced signal transduction could provide critical insights into immune regulation and support the development of innovative therapeutic strategies.

Colorectal cancer (CRC), ranked as the globe's third leading malignancy. Despite advancements in therapeutic approaches, the mortality rate remains distressingly high for those afflicted with advanced stages of the disease. Ferroptosis is a programmed form of cell death. The ways of ferroptosis mainly include promoting the accumulation of cellular ROS and increasing the level of cellular Labile iron pool (LIP). Immunosenescence is characterized by a gradual deterioration of the immune system's ability to respond to pathogens and maintain surveillance against cancer cells. In CRC, this decline is exacerbated by the tumor microenvironment, which can suppress the immune response and promote tumor progression. This paper reviews the relationship between iron prolapse and immune senescence in colorectal cancer, focusing on the following aspects: firstly, the different pathways that induce iron prolapse in colorectal cancer; secondly, immune-immune senescence in colorectal cancer; and lastly, the interactions between immune senescence and iron prolapse in colorectal cancer, e.g., immune-immune senescent cells often exhibit increased oxidative stress, leading to the accumulation of ROS, and consequently to lipid peroxidation and induction of iron-induced cell death. At the same time, ferroptosis induces immune cell senescence as well as alterations in the immune microenvironment by promoting the death of damaged or diseased cells and leading to the inflammation usually associated with it. In conclusion, by exploring the potential targets of ferroptosis and immune senescence in colorectal cancer therapy, we hope to provide a reference for future research.

Aging and cancer share common cellular hallmarks, including cellular senescence, genomic instability, and abnormal cell death and proliferation, highlighting potential areas for therapeutic interventions. Recent advancements in targeted protein degradation technologies, notably Proteolysis-Targeting Chimeras (PROTACs), offer a promising approach to address these shared pathways. PROTACs leverage the ubiquitin-proteasome system to specifically degrade pathogenic proteins involved in cancer and aging, thus offering potential solutions to key oncogenic drivers and aging-related cellular dysfunction. This abstract summarizes the recent progress of PROTACs in targeting critical proteins implicated in both cancer progression and aging, and explores future perspectives in integrating these technologies for more effective cancer treatments.

Hypoxia (insufficient O) is a pivotal factor in cancer progression, triggering genetic, transcriptional, translational and epigenetic adaptations associated to therapy resistance, metastasis and patient mortality. In this review, we outline the microenvironmental origins and molecular mechanisms responsible for hypoxic cancer cell adaptations in situ and in vitro, whilst outlining current approaches to stratify, quantify and therapeutically target hypoxia in the context of precision oncology.

Aging is associated with stereotyped changes in the tissue microenvironment that increase susceptibility to diseases of the elderly, including organ fibrosis and cancer. From a tissue perspective, fibrosis and cancer can both be viewed as non-healing wounds with pathogenic activation of tissue repair pathways in the stroma. If fibrosis and cancer represent an example of the convergent evolution of maladaptive stromal responses in distinct pathologies, what are the analogous cell types that might emerge in both diseases that share similarities in identity and function? In this review, we explore how senescent fibroblasts form a nexus that connects the aging organ with both fibrosis and cancer. The advent of single cell sequencing, coupled with improved detection of cell types with senescent traits in vivo, have allowed us to identify senescent fibroblasts with similar identities in both fibrosis and cancer that share pro-fibrotic programs. In addition to their ability to reorganize the extracellular matrix in diseased states, these pro-fibrotic senescent fibroblasts can also promote epithelial reprogramming and immune rewiring, which drive disease progression in fibrosis and cancer. Finally, the identification of common pathogenic cell types in fibrosis and cancer also presents a therapeutic opportunity to target both diseases with a shared approach.

Immunotherapy has revolutionized the management of various types of cancers, even those previously deemed untreatable. Nonetheless, these medications have been associated with inflammation and damage across various organs. These challenges are exemplified by the adverse cardiovascular impacts of cancer immunotherapy, which need comprehensive understanding, clarification, and management integrated into the overall care of cancer patients. Numerous anticancer immunotherapies have been linked to the prevalence and severity of cardiovascular toxicity. These challenges emphasize the importance of conducting fundamental and applied research to elucidate disease causes, discover prognostic indicators, enhance diagnostic methods, and create successful therapies. Despite the acknowledged importance of T cells, there remains a knowledge gap regarding the inciting antigens, the reasons for their recognition, and the mechanisms of how they contribute to cardiac cell injury. In this review, we summarize the molecular mechanism, epidemiology, diagnosis, pathophysiology and corresponding treatment of cardiovascular toxicity induced by immunotherapy, including immune checkpoint inhibitors (ICIs), adoptive cell therapies (ACT), and bi-specific T-cell engagers (BiTEs) among others. By elucidating these aspects, we aim to provide a better understanding of immunotherapies in cancer treatment and offer guidance for their clinical application.

Aging is a significant risk factor for cancer which is due, in part, to heightened genomic instability. Mitotic surveillance proteins such as BubR1 play a pivotal role in ensuring accurate chromosomal segregation and preventing aneuploidy. BubR1 levels have been shown to naturally decline with age and its loss is associated with various age-related pathologies. Sirtuins, a class of NAD-dependent deacylases, are implicated in cancer and genomic instability. Among them, SIRT2 acts as an upstream regulator of BubR1, offering a critical pathway that can potentially mitigate age-related diseases, including cancer. In this review, we explore BubR1 as a key regulator of cellular processes crucial for aging-related phenotypes. We delve into the intricate mechanisms through which BubR1 influences genomic stability and cellular senescence. Moreover, we highlight the role of NAD and SIRT2 in modulating BubR1 expression and function, emphasizing its potential as a therapeutic target. The interaction between BubR1 and SIRT2 not only serves as a fundamental regulatory pathway in cellular homeostasis but also represents a promising avenue for developing targeted therapies against age-related diseases, particularly cancer.

Increasing lifespans and external environmental factors have contributed to the increase of age-related diseases, particularly cancer. A decrease in immune surveillance and clearance of cancer cells is the result of immunosenescence, which involves the remodeling of immune organs, the changes and functional decline of immune cell subsets, in association with systemic low-grade chronic inflammation. Stem cells aging in bone marrow and thymic involution are the most important causes of immunosenescence. Senescent cancer cells promote the differentiation, recruitment, and functional upregulation of immune-suppressive cell subsets e.g. regulatory T cells (Tregs), myeloid-derived suppressor cell (MDSC), tumor-associated macrophages (TAMS) through senescence-associated secretory phenotype (SASP) further exacerbating the immunosuppressive microenvironment. For digestive system cancers, age-related damage to the intestinal mucosal barrier, the aging of gut-associated lymphoid tissue (GALT), exposure to xenobiotic stimuli throughout life, and dysbiosis make the local immune microenvironment more vulnerable. This article systematically reviews the research progress of immunosenescence and immune microenvironment in digestive system cancers, as well as the exploration of related therapy strategies, hoping to point out new directions for research in the digestive system cancers.