For decades, cancer has been primarily explained through two lenses: genetic changes within cells and environmental risk factors such as tobacco, radiation, and chemical exposure. However, a third, often overlooked player is gaining prominence: chronic inflammation associated with aging, or “inflammaging.” This process, characterized by a persistent low-grade inflammatory response in the body, may be one of the most potent underlying mechanisms behind the increasing diagnosis of various tumors in older adults.
Dr. Miriam Merad, an immunologist and director of the Precision Immunology Institute at Mount Sinai, is a leading figure in this field. Her team has observed that as we age, the balance among different types of immune cells becomes disrupted. Instead of having vigorous and mature T cells patrolling and eliminating potential tumors, older individuals tend to accumulate an excess of inflammatory myeloid cells (such as dysfunctional monocytes and neutrophils). These cells release pro-inflammatory cytokines, like interleukin-1 (IL-1), creating a microenvironment that, rather than protecting us, favors the survival and proliferation of malignant cells.
Why is IL-1 particularly detrimental in this context? In mouse models with lung cancer, Merad and her collaborators demonstrated that high levels of IL-1 stimulated the infiltration of immunosuppressive cells within the tumor (such as M2-type macrophages) and drastically reduced the activity of CD8+ T cells—the “soldiers” responsible for detecting and destroying cancer cells. Simultaneously, IL-1 increases the production of nitric oxide and reactive oxygen species in the tumor microenvironment, damaging surrounding healthy tissue and promoting mutations in epithelial cells. This leads to two issues: 1) the tumor benefits from inflammatory signals that enable its growth, and 2) the anti-tumor immune system becomes blocked.
Merad then tested a drug already approved for rheumatoid arthritis: anakinra, an IL-1 blocker. Administering it to mice with early-stage lung tumors significantly slowed tumor progression. In some cases, precancerous lesions partially regressed. This suggests that if we can intervene in the early stages of inflammaging, we might limit cellular damage, prevent additional mutations, and ultimately delay or even prevent cancer in aging populations. When researchers combined anakinra with standard chemotherapy, the results were even more promising: reduced tumor volumes and a slightly more “anti-tumoral” microenvironment (greater presence of activated T lymphocytes).
Chronic inflammation doesn’t arise out of nowhere. Factors like the accumulation of senescent cells—old cells that stop dividing but don’t die—constantly secrete chemokines and pro-inflammatory cytokines. The liver, kidneys, and especially the bone marrow, where hematopoietic cells originate, lose efficiency: they produce precursors of immune cells that migrate to tissues and keep them in a state of permanent alert, which is metabolically costly. Additionally, the aging intestine becomes more permeable (“leaky gut”), allowing bacterial products like lipopolysaccharides (LPS) to enter the bloodstream. This leakage promotes a systemic inflammatory response, reinforcing the inflammaging phenomenon.
The effects on responses to cancer treatments are evident. In 2024, Merad’s team and others reported that older patients show lower response rates to immunotherapies based on immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1). Compared to younger patients, their immune systems no longer “ignite” effectively against tumors. On one hand, mature T cells—which used to proliferate and generate immune memory—are exhausted and exhibit “exhausted T cell” phenotypes. On the other hand, the tumor microenvironment has become so inflamed and immunosuppressive that even if we release the “brake” on lymphocytes (through anti-PD-1 drugs), they don’t find the appropriate environment to expand and attack. The combination of these phenomena contributes to older adults being at higher risk for relapses and therapeutic failure.
But all is not lost. Merad emphasizes that inflammation, unlike genetic changes, is largely reversible. Blocking key pathways—like IL-1—in mice not only halted tumor progression but also partially reversed local immunosuppression. Preliminary human trials are already evaluating the use of anakinra in combination with standard immunotherapies in non-small cell lung cancer (NSCLC) and gastrointestinal tumors. Interim results show an increase in the density of infiltrating CD8+ T lymphocytes and, in certain cases, an objective response (tumor reduction ≥ 30%) in older patients who had previously failed to respond to ICI alone.
Beyond measuring inflammatory markers in the blood (e.g., IL-6, IL-1β, or C-reactive protein)—which can predict risk—Merad’s team is exploring combinations of anti-inflammatory drugs, gut microbiota modulators, and immune-stimulating therapies. In mice, a diet rich in short-chain fatty acids (SCFAs)—bacterial products from fiber fermentation—reduces markers of immune senescence and improves the efficacy of anti-PD-1. This opens the door to nutritional interventions and prebiotics designed to counteract “leaky gut” and rebalance the inflammatory response.
In parallel, chronic inflammation also creates niches for the accumulation of mutations. A recent Harvard study examined healthy breast tissue from women aged 65 to 85 and found mutation loads four times higher than in women in their 40s, in key genes related to cell regulation (TP53, PIK3CA). Most of these mutations wouldn’t have arisen without a constant inflammatory environment that generates oxidative stress, damages DNA, and activates erroneous repair pathways. In other words, inflammaging also becomes fertile ground for the emergence of precancerous clones, even years before a clinically detectable tumor diagnosis.
Figure 1. Inflammaging leads to reduced T cell function and increased myeloid cell activity. Elevated IL-1 promotes oxidative stress, DNA damage, and recruitment of M2 macrophages, creating a tumor-supportive environment. Exhausted T cells fail to respond effectively to immune checkpoint inhibitors, limiting therapeutic success in older patients.
Dr. Merad’s research aligns with other groups pointing to nicotinamide adenine dinucleotide (NAD+) as a central factor in cellular aging. When NAD+ levels decline, mitochondria function poorly, and immune cells lose clarity in signaling to differentiate “self” from “non-self.” In preclinical models, supplementing NAD+ precursors (like nicotinamide riboside) helps restore mitochondrial function in aged T lymphocytes and increases their cytotoxic capacity against tumor cells. These findings could soon translate into clinical trials, combining NAD+ precursors with ICI in subgroups of older patients.
As of mid-2025, the oncology community is rethinking how to approach cancer in older adults. Parameters like “weight, performance status,” and specific mutations are no longer sufficient: it’s now essential to assess the patient’s systemic inflammatory profile and immune health. Blood biomarker tests, gut microbiome analysis, and immune senescence assays (e.g., markers of exhausted T lymphocytes) are coming to the forefront. In fact, several phase III trials are being designed to stratify older patients based on their level of inflammaging: those without marked chronic inflammation will receive immunotherapy as currently indicated; while those exhibiting high levels of IL-1β or IL-6 before treatment will be assigned to an experimental arm that adds anti-inflammatory modulators (anakinra or tocilizumab) before initiating ICI.
In summary, the findings of Dr. Merad and colleagues—and other groups at institutions like Stanford, Harvard, and the Karolinska Institute—call for a transformation in the oncological approach for the aging population. Chronic inflammation ceases to be background “noise” and emerges as a central driver of cancer: it fosters mutations, creates immunosuppressive environments, and erodes the anti-tumor response. Recognizing this scenario offers us a window of opportunity: to address cancer not only from the tumor’s genetics but also from the patient’s immunological ecology. In practice, this means measuring inflammatory levels, modulating them with already available drugs (anakinra, IL-6 inhibitors), optimizing nutrition (promoting SCFAs), and enhancing aged T lymphocytes with metabolites like NAD+. Only then can we offer our older patients not just more time, but also a better quality of life.
Main Reference:
McKay, B. (2024). How ‘Inflammaging’ Drives Cancer—and Points to New Treatments. The Wall Street Journal.
Available at: https://www.wsj.com/health/inflammation-cancer-rates-treatment-542513e7
