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.

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.

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.

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.

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.

Aims: Recurrent and uncontrolled inflammation of the colon may cause inflammatory bowel diseases (IBD), which are strongly associated with the onset of colitis-associated cancer (CAC). However, the molecular mechanisms linking inflammation, dysregulated growth, and tumorigenesis remain unclear. This study aims to determine the role of the N⁶-methyladenosine (m⁶A) reader YTH m⁶A RNA binding protein 1 (Ythdf1) in regulating colitis severity and CAC development.

Methods: Ythdf1-deficient and wild-type mice were subjected to dextran sodium sulfate (DSS)-induced colitis to evaluate disease severity, epithelial survival, goblet cell and mucus preservation, and inflammatory signaling. m⁶A-dependent regulation of Jak1 mRNA and the Il6-Jak1-Stat3 pathway activation was assessed through molecular analyses. Additionally, an azoxymethane (AOM)/DSS model was used to determine the impact of Ythdf1 loss on CAC development.

Results: Ythdf1 deficiency significantly worsened DSS-induced colitis, with increased epithelial damage, loss of goblet cells and mucus, impaired epithelial survival, and reduced Stat3 activation. Mechanistically, Ythdf1 recognized m⁶A-modified Jak1 mRNA and enhanced Jak1 protein expression, thereby maintaining the Il6-Jak1-Stat3 signaling during inflammatory stress. Despite aggravating colitis, Ythdf1 loss markedly suppressed CAC progression and reduced tumor burden.

Conclusion: Ythdf1 is a key regulator of intestinal homeostasis, maintaining the Il6-Jak1-Stat3 signaling to protect against colitis while paradoxically promoting CAC progression. These findings identify Ythdf1 as a context-dependent modulator of intestinal inflammation and tumorigenesis, highlighting its therapeutic potential in IBD and CAC.

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.

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.

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.