Two Carcinogen-Resistant Mole-Rats, Two Very Different Immune Playbooks

The Damaraland mole-rat, a eusocial subterranean rodent that can live roughly 23 years, has joined its famous cousin, the naked mole-rat, in the small club of mammals that shrug off chemical carcinogens. In a study published in GeroScience, researchers report that Damaraland mole-rats treated with two well-established carcinogenic regimens developed no tumors over observation periods stretching beyond three years, while laboratory mice treated in parallel developed tumors rapidly. Yet the most surprising result is not the shared resistance itself but what lies beneath it: the two mole-rat species, separated by roughly 31 million years of evolution, appear to defend their tissues in fundamentally different immunological ways.

The naked mole-rat, Heterocephalus glaber, is the longest-lived rodent known, with a maximum lifespan exceeding 40 years and only a handful of tumors ever recorded among several thousand pathological autopsies. Earlier work by the same team, led by Kyoko Miura of Kumamoto University, had shown that naked mole-rats form no tumors after injection of the carcinogen 3-methylcholanthrene or after the classic two-stage DMBA/TPA skin carcinogenesis protocol. What remained unclear was whether this resistance was a quirk of one lineage or a broader feature of the African mole-rat family, the Bathyergidae, whose members share traits such as high-molecular-mass hyaluronan, enhanced DNA repair gene expression, and the loss of necroptosis, a pro-inflammatory form of programmed cell death.

To find out, the researchers injected 3-methylcholanthrene under the dorsal skin of Damaraland mole-rats and mice, adjusting doses for body weight, so mice received 0.4 milligrams and mole-rats 2.4 milligrams. Five of ten mice given the higher dose developed tumors within 18 weeks, and nine of ten mice given a lower dose developed fibrosarcomas within 21 weeks. None of the nine Damaraland mole-rats developed tumors. Six of those animals remained alive and tumor-free after 197 weeks, roughly 3.8 years, of observation. Histopathological examination of three animals euthanized at 54 weeks revealed no precancerous abnormalities or increased cell proliferation at the injection sites, only mild nuclear atypia in the epidermis and focal fibrotic thickening of connective tissue in two individuals.

The second regimen applied the tumor initiator DMBA to the skin, followed by twice-weekly applications of the promoter TPA. Within 45 weeks, six of seven mice had developed papillomas large enough to end the experiment. All seven Damaraland mole-rats stayed tumor-free, and when TPA treatment was continued until weeks 184 to 208, with monitoring extending to weeks 203 to 227, none ever formed a tumor. Biopsies taken at 53 weeks showed sporadic dysplastic lesions with multilayered, Ki67-positive cells and nuclear atypia in the epidermis, but no significant overall increase in proliferation and no progression toward malignancy.

Importantly, the carcinogens did leave molecular fingerprints. One week after 3MC injection, and after a single round of DMBA/TPA, Damaraland mole-rat skin showed significant increases in cells positive for phospho-histone H2A.X, a marker of DNA double-strand breaks. Early DNA damage therefore occurs in mole-rat skin just as it does in mouse skin; the difference is that in the mole-rats this damage never progressed to tumors over the observation window. Re-examination of naked mole-rat skin likewise revealed occasional dysplastic regions and nuclear atypia years after exposure, and long-term follow-up of naked mole-rats injected with 3MC intramuscularly, or treated with DMBA/TPA, showed no tumor formation even five to eight years later.

The divergence emerged when the team examined immune cell infiltration. In mice, 3MC significantly increased the numbers of CD45-positive leukocytes, IBA1-positive macrophages, and MPO-positive neutrophils in the skin within a week. Damaraland mole-rat skin responded even more vigorously, with significant increases in CD45, IBA1, MPO, and CD3-positive T cells, and abundant resident immune cells even before treatment, at levels comparable to or exceeding those of mice. Two weeks after DMBA/TPA, the same pattern held, with marked T cell infiltration in particular. This stands in stark contrast to naked mole-rat skin, which the earlier study showed mounts only minimal immune cell infiltration after carcinogen exposure. In Damaraland mole-rats, immune infiltration even persisted at 53 to 54 weeks after treatment, with significantly elevated CD45 and IBA1-positive cells under continuous TPA exposure, yet the dysplastic lesions still never became tumors.

RNA sequencing of skin one week after 3MC exposure deepened the contrast. Mice showed the largest number of differentially expressed genes, enriched for innate immune and inflammatory pathways including type I interferon responses, pyroptosis, and tissue-remodeling metalloproteinases. Naked mole-rats instead upregulated genes involved in keratinization, such as filaggrin and small proline-rich proteins, and p53-related stress pathways, consistent with a non-inflammatory, tissue-protective strategy. Damaraland mole-rats displayed a distinctive dual program: upregulation of T cell function genes such as CD8B and ZAP70, innate immune signaling genes such as TLR3 and CXCR3, and complement components, alongside simultaneous upregulation of immunosuppressive Siglec family genes and kynurenine pathway enzymes such as IDO1. The authors interpret this as immune activation held in check by negative-feedback regulation, an environment capable of surveying for damaged or aberrant cells while restraining chronic inflammation.

Beneath these species-specific programs, the two mole-rats share a quieter common ground. Both showed constitutively lower expression of Toll-like receptors, interferon signaling genes, and IL-1 pathway components than mice, and neither activated necroptosis; the necroptosis executors RIPK3 and MLKL, highly upregulated in mice after 3MC, were absent from the mole-rat response. Because necroptosis releases damage-associated molecular patterns that fuel carcinogen-induced tumorigenesis, its loss may help keep the inflammatory milieu restrained in both species. Only 21 upregulated genes overlapped between the two mole-rats, among them HAS2, the hyaluronan synthase previously implicated in naked mole-rat cancer resistance, and several metabolic genes suggesting shared metabolic reprogramming.

The authors are careful to note the limits of the work. The observed differences are correlative, and whether the divergent immune programs causally underpin cancer resistance remains to be tested functionally. Observation periods covered about four years and focused on skin alone, and sample sizes were small, an unavoidable constraint when working with long-lived, slow-breeding animals. Anatomical factors may also contribute: Damaraland mole-rats are fur-covered and maintain a stable body temperature near 35 degrees Celsius, whereas furless naked mole-rats are heterothermic with a preferred temperature near 32 degrees, differences that could shape resident immune cell populations independently of any anti-cancer strategy.

Even with those caveats, the study broadens the picture of how nature builds a cancer-resistant mammal. African spiny mice develop only small benign tumors after prolonged DMBA/TPA treatment, and Middle East blind mole-rats resist carcinogens for months but occasionally form benign granulomas or fibrosarcomas, whereas the two African mole-rats showed no tumors across observation windows of up to four and eight years. Cancer resistance, it turns out, can ride on either suppressed inflammation, as in the naked mole-rat, or tightly regulated immune activation, as in the Damaraland mole-rat. Because chronic inflammation drives both cancer and aging in humans, understanding how these subterranean rodents balance immune activation and suppression may reveal conserved principles of immunoregulation relevant to healthy longevity far beyond the burrow.

Subject of Research: Shared cancer resistance but divergent immune responses in two long-lived African mole-rat species: the naked mole-rat and the Damaraland mole-rat

Article Title: Shared cancer resistance but divergent immune responses in two long-lived African mole-rat species: the naked mole-rat and the Damaraland mole-rat

Article References: Sekiguchi, K., Oka, K., Nagase, M., Sano, Y., Nakamoto, M., Ota, K., Nakamura, K., Kobe, M., Onoue, N., Inoue, N., Mikawa, T., Sakai, Y., Sakurai, S., Fujiwara, Y., Kawamura, Y., Yamamoto, T., Buffenstein, R., Komohara, Y., & Miura, K. (2026). Shared cancer resistance but divergent immune responses in two long-lived African mole-rat species: the naked mole-rat and the Damaraland mole-rat. GeroScience. https://doi.org/10.1007/s11357-026-02576-2

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02576-2

Keywords: Shared, cancer, resistance, divergent, immune, responses, long-lived, African, mole-rat, species, naked, Damaraland