Immunosenescence and cancer: molecular hallmarks, tumor microenvironment remodeling, and age-specific immunotherapy challenges

Aug 22, 2025Journal of hematology & oncology

Aging of the immune system and cancer: key molecular signs, changes in the tumor environment, and challenges for age-tailored immunotherapy

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Abstract

Eleven molecular hallmarks of are identified as key factors affecting immune function and cancer progression in aging populations.

Immunosenescence is associated with a decline in immune function that impacts cancer outcomes.
Genomic instability, telomere shortening, and chronic inflammation contribute to immune cell dysfunction.
Aging alters the by promoting immunosuppressive cells and metabolic changes.
Immunotherapies may be less effective in older patients due to T cell exhaustion and altered immune dynamics.
Emerging strategies, such as senolytics and metabolic interventions, could potentially rejuvenate immune responses.
Single-cell analysis reveals variations in immune cell characteristics and new therapeutic targets, such as interleukin-34.

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, the age-related decline in immune function, profoundly impacts cancer progression and therapeutic outcomes by fostering a tumor-promoting microenvironment and impairing immune surveillance. This review delineates eleven molecular hallmarks of immunosenescence, including genomic instability, telomere attrition, epigenetic dysregulation, mitochondrial dysfunction, and chronic inflammation, which collectively drive immune cell dysfunction and systemic immunosuppression. Aging reshapes the (TME) through recruitment of immunosuppressive cells, senescence-associated secretory phenotypes (SASP), and metabolic reprogramming, contributing to therapy resistance and poor prognosis in elderly patients. While immunotherapies such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell immunotherapy (CAR-T) cells show promise, their efficacy in aging populations is limited by T cell exhaustion, myeloid bias, and altered intercellular communication. Emerging strategies-including senolytics, epigenetic modulators (e.g., histone deacetylase (HDAC) inhibitor), and metabolic interventions (e.g., spermidine, nicotinamide mononucleotide (NMN))-highlight potential avenues to rejuvenate aged immunity. Single-cell multi-omics (single cell RNA-seq, single cell ATAC-seq) further unravel immune cell heterogeneity, revealing tissue-specific chromatin accessibility dynamics and novel targets like interleukin-34 (IL-34) for microglia-mediated neuroinflammation. However, challenges persist in translating preclinical findings to clinical practice, necessitating age-tailored trials and biomarker-driven approaches. By integrating mechanistic insights with translational innovations, this review underscores the urgency of addressing immunosenescence to optimize cancer immunotherapy for aging populations, ultimately bridging the gap between aging biology and precision oncology.

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Immunosenescence and cancer: molecular hallmarks, tumor microenvironment remodeling, and age-specific immunotherapy challenges

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