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

Abstract

Several exceptionally long-lived mammals show natural resistance to cancer. The longest-lived rodent, the naked mole-rat (NMR; Heterocephalus glaber) is renowned for its remarkable resistance to carcinogenesis; however, it is unclear whether other long-lived African mole-rat species are also cancer-resistant, and whether they exhibit similar responses to chemical carcinogens. Here, we demonstrate that a long-lived, close relative of the NMR, the Damaraland mole-rat (DMR; Fukomys damarensis), is also highly resistant to skin carcinogenesis induced by two different chemical carcinogens. Strikingly, DMRs developed no tumors over a period of more than 3 years. Despite sharing a cancer-resistant phenotype, the two species exhibit markedly different immune responses. After exposure to carcinogens, DMRs show robust immune cell infiltration, whereas NMRs exhibit only minimal immune cell infiltration. At the transcriptomic level, these differences were even more pronounced. DMRs upregulated genes associated with both T cell-mediated and innate immune responses, reflecting broad immune activation, while simultaneously upregulating immunosuppressive molecules that may restrain excessive inflammatory responses. By contrast, NMRs showed limited transcriptional changes, instead engaging the keratinization and p53-related stress pathways, consistent with attenuated inflammation and potentially reflecting a distinct tissue-protective strategy. Both species, however, showed low expression of Toll-like receptor genes and loss of necroptosis induction, which may mitigate cancer-promoting tissue inflammation. Together, these findings indicate that closely related cancer-resistant African mole-rat species can exhibit divergent immune responses despite similar life-history traits and shared evolutionary history, highlighting the diversity of biological pathways associated with cancer resistance in long-lived mammals.