Introduction: The Triangle of Aging, Cancer, and Immunity
In Part 1, we explored why cancer is often described as a “disease of aging” and reviewed the historical and conceptual overlap between the hallmarks of aging and the hallmarks of cancer. In Part 2, we zoomed in on molecular and genetic mechanisms—DNA damage, telomeres, epigenetics, mitochondria, cellular senescence—and saw how they shape the context in which tumors arise.
In Part 3, we move up one level to focus on the immune system and the tumor microenvironment (TME). Aging does not just change the internal state of cells; it reshapes the body’s defense network and the local ecosystems in which tumors grow.
In this article, we will discuss:
- Immunosurveillance and immunoediting
- Immune aging (immunosenescence) and inflammaging
- How aging alters the tumor microenvironment (TME)
- Immune checkpoint inhibitors in older patients
- The impact of lifestyle (diet, exercise, infections) on immune aging
As in the previous parts, the goal is not to catalog every detail, but to provide a clear conceptual map that makes it easier to interpret research findings and clinical discussions on aging and cancer.
Cancer and Immunity: Immunosurveillance and Immunoediting
The idea that the immune system can recognize and eliminate emerging cancer cells—“cancer immunosurveillance”—has been discussed since the mid-20th century. Today, the relationship between cancer and immunity is often framed in terms of immunosurveillance and immunoediting.
Immunosurveillance: Detecting and Eliminating Abnormal Cells
Immunosurveillance refers to the ongoing process by which the immune system monitors cells and eliminates those that appear abnormal, such as virus-infected cells or pre-malignant cells. Key players include:
- T cells, especially CD8+ cytotoxic T lymphocytes
- Natural killer (NK) cells
- Antigen-presenting cells such as dendritic cells and macrophages
Cancer cells often carry mutations that create neoantigens—novel peptides not present in normal cells. In principle, these neoantigens can mark tumor cells as “non-self” and make them targets for immune attack.
Immunoediting: A Dynamic “Back-and-Forth” between Tumor and Immunity
However, the interaction between cancer and immunity is not a simple win–lose game. The concept of immunoediting breaks the process down into three phases:
- Elimination: the immune system successfully detects and destroys emerging tumor cells
- Equilibrium: some tumor cells survive and coexist with immune pressure in a dynamic balance
- Escape: clones that evade immune detection or suppression expand, leading to clinically apparent cancer
Aging influences each of these phases. As immune function declines and chronic inflammation increases, the elimination phase may become less effective, equilibrium may be tilted in favor of tumor persistence, and escape becomes more likely.
Basics of Immune Aging: How the Hematopoietic and Lymphoid Systems Change
Immune aging (immunosenescence) encompasses age-related changes throughout the immune system. Here we highlight a few core elements: hematopoietic stem cells, the thymus, peripheral T and B cells, and innate immunity.
Hematopoietic Stem Cells and Bone Marrow
All blood cells originate from hematopoietic stem cells (HSCs) in the bone marrow. With age, HSCs undergo several changes:
- Their number may increase, but self-renewal and differentiation quality decline
- Differentiation shifts toward myeloid lineages at the expense of lymphoid lineages
- Clonal hematopoiesis—expansion of HSC clones carrying specific mutations—becomes more frequent
These changes contribute to reduced immune responsiveness, increased risk of infections, and a higher likelihood of hematologic malignancies such as leukemia and lymphoma.
Thymic Involution and Narrowing of the T Cell Repertoire
T cells are “educated” and mature in the thymus. After puberty, the thymus gradually shrinks and loses functional tissue—a process known as thymic involution. As a result:
- Production of new naive T cells declines
- Existing memory T cells expand to maintain overall T cell numbers
- The diversity of the T cell receptor repertoire decreases, limiting recognition of new antigens
This narrowing of the T cell repertoire compromises the ability to respond to novel pathogens and emerging tumor neoantigens, and contributes to skewed, sometimes dysregulated immune responses.
B Cells and Antibody Responses
Aging also affects B cell development and function, including class switching and somatic hypermutation. Clinically, this manifests as:
- Weaker responses to vaccines compared to younger individuals
- Reduced ability to generate high-affinity antibodies against new antigens
- Increased frequency of autoantibodies
In the context of cancer, these changes may influence the efficacy and toxicity profile of antibody-based therapies and cell therapies that rely on robust humoral and cellular responses.
Innate Immunity: Macrophages, Neutrophils, NK Cells
Innate immune cells are also altered with age. Studies have reported:
- Reduced phagocytic capacity and migration of macrophages
- Changes in neutrophil function and lifespan
- Altered cytotoxic activity of NK cells (numbers may increase, but functional quality can decline)
- Skewed pattern recognition receptor (PRR) signaling and cytokine production
These changes increase susceptibility to infections and shape the early immune response to transformed cells, thereby influencing both cancer risk and the composition of the tumor microenvironment.
Inflammaging: Chronic Low-Grade Inflammation as a Link
Alongside immunosenescence, another key concept is inflammaging—chronic, low-grade, systemic inflammation that accompanies aging.
Why Does “Silent” Inflammation Persist?
Multiple factors contribute to inflammaging:
- Metabolic disturbances such as obesity and insulin resistance
- Changes in the gut microbiota and intestinal barrier integrity
- Persistent SASP secretion from senescent cells in various tissues
- Cumulative effects of chronic infections and tissue damage
These drivers raise baseline levels of inflammatory mediators such as IL-6, TNFα, and CRP, even in the absence of acute infection.
How Inflammaging Affects Cancer
From an oncology perspective, chronic low-grade inflammation has several pro-tumor effects:
- Inflammatory cytokines can promote cell proliferation and angiogenesis, supporting tumor growth
- Increased production of reactive oxygen and nitrogen species enhances DNA damage and genomic instability
- Some inflammatory signals foster immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells (MDSCs), which blunt anti-tumor immunity
At the same time, properly controlled inflammatory responses are essential for effective tumor elimination. The problem in inflammaging is not inflammation per se, but dysregulated, chronic, low-grade inflammation that simultaneously damages tissues and impairs effective immune responses.
Aging in the Tumor Microenvironment (TME)
Tumors grow within complex microenvironments that include blood vessels, fibroblasts, immune cells, and the extracellular matrix. Aging reshapes each of these components.
Fibroblasts and Cancer-Associated Fibroblasts (CAFs)
Fibroblasts maintain tissue structure and produce extracellular matrix. With age, fibroblasts can themselves become senescent and adopt a SASP-rich, pro-inflammatory, pro-tumor phenotype. In established tumors, cancer-associated fibroblasts (CAFs):
- Secrete growth factors and cytokines that support tumor cell proliferation
- Remodel the extracellular matrix to facilitate invasion and metastasis
- Form physical and biochemical barriers that impede immune cell infiltration
Aging-related changes in fibroblasts and CAFs may contribute to the “stiffness,” treatment resistance, and altered drug distribution characteristic of tumors in older patients.
Blood Vessels, Oxygen Supply, and Aging
In aged tissues, endothelial cell function declines and microvascular architecture can become disorganized. In tumors, this can lead to:
- Patchy and inefficient blood flow
- Regions of chronic hypoxia (low oxygen)
- Fluctuations in nutrient and drug delivery
Hypoxia, in turn, fosters metabolic reprogramming, stem-like features in tumor cells, resistance to radiotherapy, and expression of immunosuppressive molecules. Thus, vascular aging and tumor angiogenesis are tightly interwoven.
Quality, Not Just Quantity, of Tumor-Infiltrating Immune Cells
Aging alters not only how many immune cells infiltrate tumors, but also what kinds and in what functional states. In older individuals, tumor-infiltrating immune cells may show:
- Increased proportions of exhausted T cells with diminished cytotoxic capacity
- Higher levels of regulatory T cells (Tregs) and MDSCs that suppress anti-tumor immunity
- A shift in macrophage polarization toward M2-like, tissue-repair and immunosuppressive phenotypes
These shifts can influence both spontaneous anti-tumor immunity and responses to immunotherapy, including checkpoint blockade.
Immune Checkpoint Inhibitors in Older Patients
PD-1/PD-L1 and CTLA-4 checkpoint inhibitors have transformed treatment for many cancers. Their use in older patients raises important questions about both efficacy and safety in the context of immune aging.
Does Immune Aging Necessarily Mean Weaker Responses?
Based on immunosenescence, it is natural to worry that older patients might derive less benefit from checkpoint inhibitors. However, clinical data are not so straightforward. Several analyses suggest that:
- Chronological age alone does not reliably predict reduced efficacy of checkpoint inhibitors
- In some settings, older patients can obtain benefits comparable to, or even greater than, those of younger patients
This implies that tumor-intrinsic factors (mutational burden, PD-L1 expression, antigenicity), TME composition, comorbidities, and functional status are at least as important as age itself. A nuanced approach is needed.
Safety, Frailty, and Individualization
On the safety side, older patients may be more vulnerable to immune-related adverse events (irAEs) and may have less physiological reserve to recover from severe toxicities. This highlights the importance of:
- Assessing functional age (frailty, organ function, daily activities) rather than relying on chronological age alone
- Closer monitoring for irAEs and proactive management strategies
- Designing trials that adequately include older adults to build robust evidence
In short, immune aging does not automatically exclude patients from immunotherapy, but it does demand more individualized risk–benefit assessment and supportive care planning.
Lifestyle and Immune Aging: Diet, Exercise, and Infections
Immune aging and inflammaging are shaped not only by genetics and time, but also by lifestyle and environmental exposures.
Diet: Connecting Metabolism, Inflammation, and Cancer
Diets rich in saturated fats, refined sugars, and excess calories promote obesity, fatty liver, and insulin resistance, all of which contribute to chronic inflammation. Adipose tissue secretes adipokines and inflammatory cytokines that form part of the inflammaging landscape and can influence cancer risk and progression.
Conversely, dietary patterns such as the Mediterranean diet—emphasizing vegetables, fruits, whole grains, fish, and olive oil—are associated with lower levels of inflammatory markers and reduced cardiovascular risk. These patterns may also have favorable effects on immune aging and cancer risk, although the exact mechanisms are still being elucidated.
Exercise: A Hub Linking Muscle, Bone, and Immunity
Regular moderate exercise—both aerobic and resistance training—can:
- Reduce visceral fat and improve insulin sensitivity
- Stimulate myokine release from skeletal muscle with anti-inflammatory effects
- Improve microcirculation in bone marrow and lymphoid tissues
Many epidemiologic studies link habitual physical activity with lower incidence and improved outcomes in several cancers. While extreme overtraining can transiently suppress immunity, consistent moderate exercise seems to support healthier immune aging and may indirectly influence tumor biology.
Infections, Vaccines, and the Aging–Cancer Interface
Infections form an important bridge between aging and cancer. Classic examples include:
- Helicobacter pylori and gastric cancer
- Hepatitis B and C viruses and hepatocellular carcinoma
- Human papillomavirus (HPV) and cervical and head-and-neck cancers
As immune aging progresses, control of chronic infections may become more difficult. At the same time, vaccines that prevent or mitigate such infections—HPV, HBV, and others—are powerful tools for cancer prevention. For older adults, vaccines like pneumococcal and zoster vaccines are also important, reducing infection-related complications that can destabilize health and complicate cancer care.
Conclusion: Immune and Microenvironmental Aging as Hidden Background Factors
In Part 3, we examined how aging shapes the immune system and tumor microenvironment, and how these changes influence cancer:
- Immunosurveillance and immunoediting: the immune system constantly patrols for transformed cells, while tumors evolve escape strategies; aging shifts this balance.
- Immune aging: changes in HSCs, the thymus, T and B cells, and innate immunity reduce responsiveness to new antigens and increase vulnerability to cancer and infections.
- Inflammaging: chronic low-grade inflammation promotes DNA damage, proliferation, and immunosuppression, contributing to cancer risk and progression.
- Aging in the TME: fibroblasts, blood vessels, and immune cells age and change, creating microenvironments that can either restrain or support tumor growth and immune evasion.
- Checkpoint inhibitors and older patients: chronological age alone is not a reliable guide; functional age and individual aging profiles are crucial for treatment decisions.
- Lifestyle and immune aging: diet, exercise, infections, and vaccination shape immune aging and inflammaging, thereby influencing cancer risk and treatment response.
Immune and microenvironmental aging are not directly visible on routine scans or lab tests, yet they profoundly influence whether cancer develops, what kind of cancer it is, and how it responds to therapy. As precision oncology advances, integrating these “hidden background factors” with genomic and molecular information will become increasingly important.
In Part 4, we will shift to an organ- and tissue-level perspective. We will explore why different organs age and develop cancer at different rates, and how sex differences and reproductive aging (ovarian and testicular aging) modulate cancer risk and biology.
My Thoughts
Adding the lens of immune aging and the tumor microenvironment reveals just how much complexity is contained in the simple phrase “aging increases cancer risk.” Cancer is not merely a problem of mutated cells; it is an emergent property of interactions between those cells and the changing landscape of immunity, inflammation, stroma, and vasculature that surrounds them.
What I find particularly intriguing is that immune aging is not just a story of “decline,” but also one of “reconfiguration.” The shift from lymphoid to myeloid bias, from naive to memory-dominated T cell pools, and from acute to chronic low-grade inflammation reflects long-term adaptations to recurring stress and infection. These adaptations serve us for decades, but beyond a certain threshold they can contribute to cancer, atherosclerosis, neurodegeneration, and other age-related diseases. Identifying where that threshold lies—and when and how to intervene—may be one of the central challenges at the interface of geroscience and oncology.
In clinical practice, the question is no longer simply whether immunotherapies “work” in older patients, but for whom, at what time, and at what intensity. As we improve our ability to characterize the evolving profiles of immunity, inflammation, and the microenvironment—through biomarkers, imaging, and digital tools—we may move toward truly integrated strategies that treat cancer while also modulating the underlying aging processes that shape it.
Throughout this series, my aim is to provide a shared conceptual framework that allows basic scientists, clinicians, policymakers, and investors to talk about aging and cancer in a common language, while still respecting the complexity of each domain.
This article has been edited by the Morningglorysciences team.
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