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.

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.

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.

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.

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.

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 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.

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.