Immunosenescence is a biological process accompanying ageing, characterized by increased susceptibility to infections, reduced vaccine efficacy, and the development of chronic low-grade inflammation. Although immunosenescence is systemic, the relative contribution and compensability of each organ in the adaptive immune axis remain debated. We consolidate current evidence supporting a thymus-centric model of immune ageing. In this model, early and progressive thymic involution, marked by thymic epithelial cell attrition, FOXN1 decline, and architectural disruption, emerges as the principal constraint on de novo naive T‑cell production and T-cell receptor (TCR) repertoire renewal. In contrast, age‑related changes in bone marrow and spleen often exhibit partial compensability through peripheral redistribution and clinical interventions, sustaining counts but not restoring de novo diversity. We evaluate mechanisms of thymic involution, inter-organ communication, and cross-species parallels, identifying shared features across animal models. Quantitative readouts, including age-associated declines in sjTRECs and TCR-β repertoire diversity, further support the thymus-centricity. Clinically, constrained thymopoiesis may undercut vaccine responsiveness and reduce the efficacy of cancer immunotherapies (chimeric antigen receptor T-cell and immune checkpoint inhibitors) in older adults. We assess genetic, pharmacological, and bioengineering strategies to preserve or restore thymic function and outline translational paths and endpoints for future trials.

Background: DNA methylation patterns are established during development and are propagated in a cell type specific manner, but these patterns may become aberrant during aging and cancer. Regions of alternating high and moderate to low levels of DNA methylation exist along all chromosomes in human cells. It is unclear how these distinct DNA methylation blocks are established. Most of the prior work in this area has been performed with mouse embryonic stem cells.

Methods: Using whole genome bisulfite sequencing and chromatin-immunoprecipitation sequencing, we have profiled DNA methylation at single base resolution and various histone modifications in human bronchial epithelial cells.

Results: We found that many regions of lower DNA methylation (< 50%) are characterized by presence of the Polycomb repressive complex 2 (PRC2) mark, histone H3K27 trimethylation, but less so by the PRC1 mark histone H2AK119 monoubiquitylation. These same PRC2-marked regions also showed a depletion of histone H3K36 di- and tri-methylation.

Conclusion: Since H3K36me2 and H3K36me3 are recognized by the reader domains of the DNA methyltransferases DNMT3A and DNMT3B, and H3K36 methylation is a block to the PRC2 methyltransferases, these two types of crosstalk may explain the stable maintenance and antagonism between H3K27me3 and broad DNA methylation domains. However, methylated CpG islands are depleted of H3K36me2 and show a different relationship between DNA methylation and H3K36me2 deposition compared to non-CpG island regions. The data give insight into how DNA methylation patterns are established in human cells. We discuss these findings and their potential relevance for altered DNA methylation patterns seen in aging tissues and in cancer cells.

Background: The outcomes of older adults with cancer are usually worse than those of their younger counterparts. Several randomised trials have demonstrated benefits of a comprehensive geriatric assessment (CGA) in older patients undergoing systemic cancer therapy. Despite that, CGA is not implemented into routine care in Germany and data on its efficacy and feasibility within the German healthcare system are missing.

Methods: This prospective, bicentric cohort study will assess the feasibility of CGA implementation into routine care for older adults with cancer in Germany. Patients ≥ 65 years with a positive geriatric screening (G8) and newly diagnosed cancer or progressive disease prior to a new treatment line undergo a CGA as part of their routine care. Patients who consent to participate in the study receive a follow-up call after three months to assess functional measures, and their (routine) CGA data are analyzed thereafter. CGA results are presented during the multidisciplinary team meeting to inform treatment recommendations provided by primary healthcare providers (pHCP; e.g., oncologists, gynecologists, urologists). pHCP are further evaluated for their satisfaction with CGA implementation and whether its results have influenced their recommendations. The primary endpoint is to estimate the patients’ willingness to participate with an accuracy of ± 7.5%. Secondary endpoints focus on additional feasibility measures and patient preferences.

Conclusion: This study will assess the feasibility of CGA implementation into routine care for older cancer patients. Its results will provide the framework to design a larger subsequent trial to assess the efficacy and cost effectiveness of CGA implementation in Germany.

Clinical trial registration number: DRKS00035569

DNA end resection is a pivotal process that governs repair pathway choice following double-strand breaks and is essential for maintaining genomic stability. Traditionally considered an enzyme-driven cascade regulated by post-translational modifications, recent insights have revealed an additional layer of control mediated by liquid–liquid phase separation (LLPS). Our recent findings identify LLPS as a key organizing principle in DNA end resection through the ERCC6L2–RNF138–CtIP axis, in which ERCC6L2-driven condensates stabilize CtIP and modulate the extent of resection. This perspective discusses the emerging concept of LLPS as a regulatory mechanism in DNA repair, highlighting key mechanistic questions regarding condensate formation, spatial coordination, and pathway choice. We further explore the broader implications of dysregulated phase separation in aging and cancer, and consider how pharmacological modulation of LLPS could be leveraged to enhance therapeutic responses to genotoxic stress.

Growth Differentiation Factor 15 (GDF15), a member of the transforming growth factor-beta superfamily, is highly expressed in response to cellular stress, ageing, and various pathological conditions. As a key component of the senescence-associated secretory phenotype, it plays important roles in modulating inflammation, mitochondrial dysfunction, energy metabolism, and appetite. It signals through the glial-derived neurotrophic factor receptor alpha-like receptor in the brainstem to suppress appetite and modulate energy balance. Increasing evidence supports that GDF15 exhibits dual and context-dependent functions in cancer, contributing to both tumor suppression and progression through its regulation of cellular proliferation, metastasis, and interactions within the tumor microenvironment. Elevated GDF15 levels have been observed in cardiovascular diseases, metabolic disorders, neurodegenerative diseases, and numerous malignancies, making it a potential biomarker and therapeutic target for a spectrum of age-related and pathological conditions, including cancer. Emerging therapeutic strategies targeting GDF15 encompass the use of agonists for obesity and antagonists for cachexia, either alone or in combination with immunotherapy, reflecting its complex role in disease. A comprehensive understanding of its context-dependent roles may shed light on fundamental disease mechanisms, offering a foundation for the development of innovative and personalized therapeutic approaches.

Radiation therapy (RT) is a cornerstone of cancer management, required in approximately half of all cancer cases, and is particularly relevant for older adults, who constitute the majority of oncology patients. Despite its localized nature and generally favorable toxicity profile, RT remains underutilized in this population, often due to age-related biases, comorbidities, or the limited integration of geriatric assessment into treatment planning. This review examines the evolving role of RT as an age-inclusive modality, highlighting innovations such as intensity-modulated and stereotactic techniques that enable more conformal, less toxic, and increasingly personalized regimens for older adults. Special attention is given to the challenges of frailty, cognitive impairment, and movement disorders, which may complicate treatment delivery and necessitate tailored adaptations. The role of comprehensive geriatric assessment and frailty screening tools is critically appraised, with emphasis on their predictive value in identifying treatment-limiting vulnerabilities and supporting shared decision-making. The review underscores the need to shift from age-based to function-based treatment paradigms, advocating for greater inclusion of older adults in clinical trials and for a multidisciplinary approach that aligns oncologic goals with patient priorities. When appropriately tailored, RT provides a safe, effective, and goal-concordant treatment option for older adults, and its optimized integration into geriatric oncology care is essential to meet the needs of an aging global population.

Advancing age substantially increases cancer risk, primarily due to progressive biological alterations over time. With the global population aging rapidly, the incidence of cancer is also rising. In cancer immunotherapy, patient age is emerging as a critical determinant for both identifying and predicting responses to immune checkpoint inhibitors. Aging is accompanied by significant changes in the immune system, notably a decline in T-cell function and a reduction in tumor-infiltrating lymphocytes, which collectively reshape the tumor microenvironment and weaken antitumor immunity. Immune senescence compromises the ability to recruit and maintain functional TIL activity, thereby limiting the benefits of immune checkpoint inhibitors therapy. Furthermore, senescent tumor cells influence their surroundings by releasing a broad spectrum of pro-inflammatory cytokines and chemokines, a phenomenon termed the senescence-associated secretory phenotype, while simultaneously upregulating immune inhibitory markers such as PD-L1. In addition, age-related immune dysregulation exacerbates cellular exhaustion, leading to abnormal expression of key biomarkers that govern immune checkpoint inhibitors efficacy and ultimately attenuating antitumor immune responses. This perspective discusses the mechanisms through which aging alters systemic immunity and the tumor microenvironment, thereby reducing immunotherapy effectiveness. By integrating current mechanistic insights into the interplay between aging and cancer immunobiology, we highlight potential aging-related biomarkers that may improve therapeutic strategies in geriatric oncology. A deeper understanding of these interactions is essential for developing personalized immunotherapeutic approaches tailored to the unique needs of elderly cancer patients.

The treatment of early invasive breast cancer in older patients poses unique challenges due to the distinct biological, clinical, and psychosocial complexities associated with aging. As the population of breast cancer patients aged 70 years and older continues to grow, their persistent underrepresentation in clinical trials remains a major obstacle to evidence-based treatment decision-making. To support the development of a more effective, personalized, and patient-centered approach to systemic therapy, this review outlines the biological features of breast cancer in older women, synthesizes current evidence on neoadjuvant and adjuvant systemic therapies, and discusses strategies for individualized treatment decision-making. Key recommendations include the use of hormonal therapy as the standard of care for hormone receptor positive breast cancer, neoadjuvant therapy primarily when tumor downstaging is desired, and chemotherapy or anti-human epidermal growth factor receptor 2 therapy for relatively fit older patients with high-risk subtypes. Additionally, bisphosphonates may help preserve bone health and reduce recurrence risk. Novel targeted therapies such as cyclin-dependent kinase 4 and 6 inhibitors and immune checkpoint inhibitors show promise, though further studies are needed to confirm their safety and efficacy in older populations. Comprehensive geriatric assessments are essential for identifying patient frailty and vulnerabilities, while predictive tools such as the Cancer and Aging Research Group Breast Cancer model can help assess toxicity risk. In this population, competing risks of non-cancer-related mortality may reduce the absolute benefit of systemic treatment. For patients with elevated risks of other-cause mortality, the potential survival benefit of cancer therapy may be negligible. Predictive models that account for competing mortality, such as the PORTRET tool, can facilitate personalized and shared decision-making.

It is becoming increasingly clear that the tumour microenvironment (TME) adopts a changing and increasingly complex landscape as tumours evolve. Central to the TME, and alongside malignant cells, are tissue resident and recruited macrophages, other immune cells, and endothelial cells, with the latter critical for angiogenesis and tumour development. Tumour vessels provide oxygen and nutrients and are portals for immune cells. Tumour cells, immune cells and endothelial cells engage in multi-directional crosstalk that untimately influence tumour progression and treatment responses. Adding to complexity, the TME often consists of oxygenated, and oxygen deprived or hypoxic regions, with the latter significantly contributing to disease progression and treatment resistance. However, the function of immune cells and endothelial cells change with ageing, and this underexplored area likely influences the aged TME and disease outcomes in the elderly. Solid cancers such as mesothelioma with known carcinogen exposure (asbestos) take decades to reach a diagnosable size, often emerging in people aged 60 years or more. Here, we discuss the influence of ageing on the function of tumour-associated immune cells, focussing on macrophages, and their possible interactions with endothelial cells, and how this might impact the evolving mesothelioma TME in elderly people.

Aims: The combination of CDK4/6 inhibitors and endocrine therapy (ET) is a standard first-line therapy for hormone receptor positive (HR+)/HER2- metastatic breast cancer (mBC). Preliminary data suggest that CDK4/6 inhibitors can alter the host immune function and stimulate tumor cell-directed immunity. However, clinical data are scarce, and no data exist about the impact of age and frailty on this phenomenon.

Materials and Methods: This biomarker substudy of the RibOB trial evaluated the impact of ribociclib and letrozole on circulating immune cell subsets and protein markers in older (≥ 70 years) patients with HR+/HER2- mBC. Peripheral blood mononuclear cell subtyping and analysis of plasma immune response and checkpoint markers were performed using flow cytometry at baseline and after three months of ribociclib + ET. Frailty status was assessed at baseline using G8 score.

Results: 20 patients (median age: 76 years, range: 70-87 years), 8 considered fit (G8 > 14), and 12 frail (G8 ≤ 14), were included. After three months of treatment, the immune subset composition showed significant increases in naïve B-, T-regulatory (Tregs), and CD4+ T-cells, while memory B-cells and Tregs were significantly decreased. In addition, consistent upregulation was seen in costimulatory receptors CD27 and CD28. Plasma immune checkpoint markers B7.2 (CD86) and PD-1 were significantly decreased. The immune subset profiles of fit versus frail persons showed no statistically significant difference.

Conclusion: The study shows that the combination of ribociclib and ET modulates the immune system in older patients, potentially reversing the age-related immunosenescence process by increasing naïve T-cell and B-cell populations and decreasing memory populations.

Clinical trial registration number: NCT03956654.

The global aging population is expected to experience a nofigure increase in cancer incidence, particularly among individuals aged 70 and older. At the same time, the extensive use of immune checkpoint inhibitors (ICIs) in cancer treatment raises questions about the influence of immunosenescence, the age-related decline in immune function, on treatment efficacy in older patients. Despite promising outcomes, resistance to immunotherapies and the occurrence of severe immune-related adverse events (irAEs) remain challenges. Limited research has explored the correlation between immunosenescence markers in peripheral blood and the tumour microenvironment (TME), frailty, and ICI response, and irAEs in older patients. This commentary explores the interrelationship between immunosenescence and immunotherapy in older and frail patients with cancer undergoing ICI therapy. Understanding the impact of immunosenescence on treatment response and irAEs, and identifying reliable biomarkers, is crucial for future research in geriatric oncology, as this will possibly facilitate patient stratification and personalized treatment approaches, ultimately improving patient outcomes while minimizing irAE-related risks.

Over the past 50 years, the world has experienced a progressive demographic shift resulting in a higher proportion of older adults in the general population. Aging itself is a complex biological phenomenon, characterized in part by changes in the immune system, known as “immunosenescence”, that make older adults more susceptible to infections, cardiovascular and autoimmune diseases, and cancer. Several strategies have been proposed to reverse immunosenescence. These include the use of hormones, cytokines, and thymic factors. Biomodulina T (BT) is a polypeptide fraction derived from bovine thymus. Intervention with BT expands naïve CD4+ T cells while decreasing the frequency of CD4+ and CD8+ T cells expressing PD1 in older adults and patients diagnosed with advanced lung cancer. This brief review aims to present the most recent evidence on the effect of BT on the immune system in older adults and patients diagnosed with advanced lung cancer.

Western and third world countries alike are experiencing population ageing with people living longer. The World Health Organization website states that ‘between 2015 and 2050, the proportion of the world's population over 60 years will nearly double from 12% to 22% reaching 2.1 billion’, and that ‘the number of persons aged 80 years or older is expected to triple between 2020 and 2050 to reach 426 million’. However, the elderly (i.e., those aged over 65 years) are 11 times more likely to develop cancer than younger people; this is illustrated by GLOBOCAN 2020 data showing that greater than 50% of people who had cancer were 65 or older in 2018. This age-related cancer emergence may in part be due to increasing dysregulation of the immune system or “immunosenescence”. Macrophages are pivotal immune cells in maintaining homeostasis and in regulating inflammatory responses during immunological insults, such as cancer, where they can perform anti-tumourigenic functions. Yet, tumour-associated macrophages are well known for their ability to promote tumour growth, with numbers often correlating to cancer progression and poorer outcomes. Macrophages contribute to this by secreting growth and angiogenic factors, and they closely interact with endothelial cells and cancer cells to help shape the tumour microenvironment. During ageing, macrophage response to environmental stimuli becomes dysregulated including impaired anti-tumour functions. Furthermore, increased number of macrophages and precursor cells are observed in lymphoid organs that can supply to tumours with ageing. Such age-related changes, including those to endothelial cells, may promote cancer development and lead to poorer cancer outcomes in elderly people. In this review, we discuss recent findings concerning how macrophages are modulated during healthy ageing and in cancer, with a focus on macrophage and endothelial cell interactions.

Aims: To assess the influence of age, cancer type, and diverse risk factors on the occurrence of postoperative pulmonary infection (PPI) in patients undergoing thoracic surgery.

Aims: To assess the influence of age, cancer type, and diverse risk factors on the occurrence of postoperative pulmonary infection (PPI) in patients undergoing thoracic surgery.

Methods: The study encompassed a cohort of 231 patients who underwent thoracic surgery. These patients were randomly divided into two groups: a modeling population comprising 185 patients and a validation population comprising 46 patients, using a random number method at a ratio of 4:1. Bivariate logistic regression models were utilized to discern variables independently predictive of postoperative complications, utilizing SPSS 26.0 (SPSS Institute, Inc., Chicago, IL, USA).

Results: The analysis unveiled that male patients, individuals aged 65 years or older, and those with a history of smoking or chronic obstructive pulmonary disease (COPD) were significantly more predisposed to the development of postoperative pneumonia. Conversely, diabetes and hypertension were not identified as risk factors. Patients with extended intubation times, higher peri-operative bleeding, prolonged hospitalization, and longer operating times displayed an increased likelihood of developing postoperative pneumonia. Intriguingly, preoperative treatments like antibiotic administration and aerosol inhalation did not demonstrate a significant reduction in postoperative pneumonia incidence. Hematological assessments revealed that low preoperative albumin (pre-ALB) levels and other specific markers served as potential indicators of postoperative pneumonia. Binary logistic regression analysis identified pulmonary function, intubation duration, intraoperative bleeding, pre-ALB levels post-operation, and the duration of preoperative hospital stay as significant risk factors. A risk model formula was formulated and validated, successfully demonstrating model construction.

Conclusion: These findings underscore the pivotal importance of taking patient age, cancer type, and various risk factors into account when predicting and managing postoperative pneumonia in thoracic surgery patients.

Immune cell aging is associated with compromised cancer immunosurveillance and reduced efficacy of some cancer immunotherapies. The ability to reverse immune cell aging to obtain more efficient anti-tumour reactive T cells would provide obvious benefits in clinical treatment. This could be achieved by acting on key fundamental cellular processes including metabolism and autophagy, which may subsequently influence T cell differentiation and effector functions. Polyamines, which can induce autophagy, have been shown both to enhance mitochondrial activity and have a direct effect on T cells. First by improving effector functions in CD8 T cells and, second, by regulating CD4 T cell differentiation. However, the exact interconnections between autophagy, mitochondrial activity and T-cell function remain to be elucidated. Most of the data on these fundamental processes have been collected from non-human systems, but fewer clinical data are available. We herein discuss the main evidence and speculate on the eventual benefit of affecting metabolism in an aged immune system to improve immunotherapy outcome.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) refers to the presence of a hematopoietic clone with a common leukemia driver mutation without diagnosis of an underlying hematopoietic disease. The prevalence of CHIP is increasing with age and is associated with pro-inflammatory states, higher risk of cardiovascular diseases (CVD) and therapy-induced leukemia. However, these CHIP-associated risks overlap with treatment-related toxicities of breast cancer therapy, which potentially supports the integration of CHIP into treatment- and survivorship plans. However, so far no data on the feasibility and acceptance of a CHIP-based aftercare are available. The aim of this pilot trial is to evaluate the feasibility to integrate pre-treatment CHIP diagnostics into the routine care of older breast cancer patients.

Materials and Methods: 80-100 patients with limited stage breast cancer aged ≥ 60 years without known hematological disease will be included. CHIP is assessed by targeted next generation sequencing from peripheral blood samples. The primary outcome measures the estimation of willingness to participate. Secondary outcome measures include evaluation of patient acceptance of the study process, potential fears in relation to CHIP-positivity, and cardiovascular risk profile of CHIP-positive versus CHIP-negative patients.

Conclusions: In case this study meets its primary endpoint, the results are used to design a larger cohort study that integrates an intensified CHIP-tailored survivorship program, in order to minimize late treatment-related toxicities and improve long-term outcomes of older breast-cancer patients.

Clinical trial registration number: German Clinical Trials Register (Deutsches Register für klinische Studien, DRKS) DRKS00031021.

Worldwide the cancer population is ageing-within a decade almost two-thirds of newly diagnosed patients will be aged 65 years and older. Despite this, the majority of oncology clinical trials continue to recruit patients who are younger and fitter than those typically encountered in clinical practice. As such, there is a lack of clinical data to guide management, particularly in those patients living with frailty and/or comorbidity. Importantly, the lack of older adults in trials also means that the subsequent translational work that underpins biomarker and therapeutic discovery may not be relevant to those we see in clinic. In this commentary, we discuss this challenge and the ways we as an Oncology community can look to address this pressing issue.

Aims: Aged individuals are significantly underrepresented in immunotherapy clinical trials for cancer. Little is known regarding the immunological and molecular dynamics that might regulate their responsiveness to immune checkpoint inhibitors (ICIs). This study aims to investigate the mechanisms affecting the response of elderly non-small cell lung cancer (NSCLC) patients to anti-PD-1 therapy.

Methods: We performed a single-cell analysis on public data from 419,107 tumor-infiltrating lymphocytes (TILs) across 11 elderly (≥ 65 years) and 5 non-elderly NSCLC patients treated with neoadjuvant anti-PD-1 therapy. The dataset, originally focused on mutation-associated neoantigen-specific T cells, was reprocessed to compare gene expression and molecular patterns associated with positive outcomes and tumor clearance between age groups.

Results: The analysis revealed that ICI responsiveness was not impaired by age, and T cell immunosenescence was observed in aged (≥ 65 years) and younger NSCLC individuals. Both elderly and young individuals produced responses with a heterogeneous molecular program associated with tumor-reactive CD8+ TILs. Specifically, T cells from elderly patients showed an enhanced expression of PDCD1 and CXCL13 (P < 0.001) in comparison to younger subjects.

Conclusion: Altogether, our findings demonstrate favorable molecular signatures in aged NSCLC individuals following anti-PD-1 treatment and suggest that the recruitment of older adults in immunotherapy clinical trials should not be dismissed solely on the grounds of age.

The outcomes of older adults with cancer are still dismal despite some progress within the last years. This is mainly due to comorbidities, overall frailty, and differences in disease biology. The better understanding of tumor biology and immunology has enabled the use of targeted therapies and immunotherapies that are potentially better tolerated than traditional chemotherapies. Several randomized trials were recently published that demonstrated a benefit of integrated onco-geriatric care including geriatric interventions on treatment-related toxicities and quality of life during cancer treatment of older adults. Furthermore, other pivotal trials adapted treatment intensities based on frailty. Despite these efforts, older and frail adults are still underrepresented in clinical trials. This leads to a major lack of an evidence-based standard of care in geriatric oncology. In this narrative review, we discuss pivotal trials, practical implications, under- and overtreatment, altered pharmacokinetics at older age, and future perspectives for geriatric oncology.

Increasing life expectancy globally results in predictions that one in six people will be > 65 years of age by 2050. Because the occurrence of most cancers is strongly associated with older age, a significant increase in the number of older adults with cancer is to be expected. It is likely that increased cancer in older adults can be explained both by the greater duration of exposure to external factors such as ultraviolet radiation, alcohol, smoking and pollution (hence modifiable by non-medical means) as well as intrinsic factors (such as metabolic stress and reactive oxygen species). These insults contribute to DNA damage and mutation that can lead to carcinogenesis if not counteracted by the appropriate repair mechanisms, or other protective strategies. Tissues from cancer-free individuals frequently contain mutations commonly observed in cancer, but these cells remain dormant until some endogenous or exogenous events promote carcinogenesis. In ageing individuals, less efficient surveillance and immune responses against cancer may represent one such event, as well as the chronic low level inflammation commonly accompanying ageing. Additionally, because of comorbidities, older patients are less robust and it is more likely that polypharmacy interferes with cancer treatment. Despite all this awareness of the impact of ageing, most cancer research, both clinical and preclinical, fails to fully consider age-associated differences in cancer occurrence and treatment, and there are very few journals specifically dedicated to publishing explorations of these issues in either the basic research or clinical context. Hence, the time has come to establish a new journal dedicated to taking a holistic approach to all aspects of cancer in older individuals. We are therefore now welcoming papers that may shed light on these increasingly important issues.