Shigeo Koyasu

Cancer does not simply develop unchecked—it strategically exploits its host with parasitic precision. From immune evasion to tissue remodeling, cancer cells mirror the survival strategies of parasitic helminths. This resemblance suggests that malignant cells have co-opted deeply conserved, evolutionarily honed tactics used by parasites to persist within their hosts. By mimicking helminths, cancer cells may also engage type-2 immune responses, traditionally associated with anti-parasitic defense, as part of the host’s attempt to control their expansion. Such parallels could also help explain why type-2 immunity, once considered tumor-promoting, has recently emerged as a potential source of tumoricidal activity. In this Perspective, we explore mechanistic parallels between cancer and helminth infection. Recognizing the parasitic nature of cancer cells not only challenges established models of oncogenesis but also reveals mechanisms that could be leveraged for therapy.

Our understanding of type 2 immunity has undergone a substantial transformation in recent years, revealing previously unknown functions. Beyond its canonical role in defence against parasitic helminth infections, type 2 immunity safeguards the host through additional mechanisms, including the suppression of excessive type 1 immune responses, regulation of tissue repair and maintenance of adipose tissue homeostasis. However, unlike type 1 immune responses, type 2 immunity is perceived as a potential promoter of tumorigenesis. Emerging evidence challenges this perspective, painting a more nuanced picture in which type 2 immunity might protect against or even actively suppress tumour growth and progression. In this Review, we explore discoveries that highlight the potential of type 2 immunity in reshaping the landscape of cancer immunotherapies.

Pulmonary fibrosis (PF), a condition characterized by inflammation and collagen deposition in the alveolar interstitium, causes dyspnea and fatal outcomes. Although the bleomycin-induced PF mouse model has improved our understanding of exogenous factor-induced fibrosis, the mechanism governing endogenous factor-induced fibrosis remains unknown. Here, we find that Ifngr1^-/-Rag2^-/- mice, which lack the critical suppression factor for group 2 innate lymphoid cells (ILC2), develop PF spontaneously. The onset phase of fibrosis includes ILC2 subpopulations with a high Il1rl1 (IL-33 receptor) expression, and fibrosis does not develop in ILC-deficient or IL-33-deficient mice. Although ILC2s are normally localized near bronchioles and blood vessels, ILC2s are increased in fibrotic areas along with IL-33 positive fibroblasts during fibrosis. Co-culture analysis shows that activated-ILC2s directly induce collagen production from fibroblasts. Furthermore, increased IL1RL1 and decreased IFNGR1 expressions are confirmed in ILC2s from individuals with idiopathic PF, highlighting the applicability of Ifngr1^-/-Rag2^-/- mice as a mouse model for fibrosis research.

Being overweight exacerbates various metabolic diseases, necessitating the identification of target molecules for obesity control. In the current study, we investigated common physiological features related to metabolism in mice with low weight gain: (1) G protein‐coupled receptor, family C, group 5, member B‐knockout; (2) gastric inhibitory polypeptide receptor‐knockout; and (3) Iroquois‐related homeobox 3‐knockout. Moreover, we explored genes involved in metabolism by analyzing differentially expressed genes (DEGs) between low‐weight gain mice and the respective wild‐type control mice. The common characteristics of the low‐weight gain mice were low inguinal white adipose tissue (iWAT) and liver weight despite similar food intake along with lower blood leptin levels and high energy expenditure. The DEGs of iWAT, epididymal (gonadal) WAT, brown adipose tissue, muscle, liver, hypothalamus, and hippocampus common to these low‐weight gain mice were designated as candidate genes associated with metabolism. One such gene tetraspanin 7 ( Tspan7 ) from the iWAT was validated using knockout and overexpressing mouse models. Mice with low Tspan7 expression gained more weight, while those with high Tspan7 expression gained less weight, confirming the involvement of the Tspan7 gene in weight regulation. Collectively, these findings suggest that the candidate gene list generated in this study contains potential target molecules for obesity regulation. Further validation and additional data from low‐weight gain mice will aid in understanding the molecular mechanisms associated with obesity.

Insulin resistance is the primary pathophysiology underlying metabolic syndrome and type 2 diabetes^1,2. Previous metagenomic studies have described the characteristics of gut microbiota and their roles in metabolizing major nutrients in insulin resistance^3–9. In particular, carbohydrate metabolism of commensals has been proposed to contribute up to 10% of the host’s overall energy extraction¹⁰, thereby playing a role in the pathogenesis of obesity and prediabetes^3,4,6. Nevertheless, the underlying mechanism remains unclear. Here we investigate this relationship using a comprehensive multi-omics strategy in humans. We combine unbiased faecal metabolomics with metagenomics, host metabolomics and transcriptomics data to profile the involvement of the microbiome in insulin resistance. These data reveal that faecal carbohydrates, particularly host-accessible monosaccharides, are increased in individuals with insulin resistance and are associated with microbial carbohydrate metabolisms and host inflammatory cytokines. We identify gut bacteria associated with insulin resistance and insulin sensitivity that show a distinct pattern of carbohydrate metabolism, and demonstrate that insulin-sensitivity-associated bacteria ameliorate host phenotypes of insulin resistance in a mouse model. Our study, which provides a comprehensive view of the host–microorganism relationships in insulin resistance, reveals the impact of carbohydrate metabolism by microbiota, suggesting a potential therapeutic target for ameliorating insulin resistance.

Group 2 innate lymphoid cells (ILC2s) were initially identified as a new type of lymphocytes that produce vigorous amounts of type 2 cytokines in adipose tissue. Subsequent studies revealed that ILC2s are present not only in adipose tissue but also in various other tissues such as lung and skin. ILC2s are generally recognized as tissue-resident immune cells that regulate tissue homeostasis. ILC2s express receptors for various humoral factors and thus can change their functions or distribution depending on the environment and circumstances. In this review, we will outline our recent understanding of ILC2 biology and discuss future directions for ILC2 research, particularly in adipose tissue and metabolic homeostasis.

Pulmonary fibrosis (PF) is characterised by inflammation and collagen deposition in the alveolar interstitium, leading to dyspnoea and death. However, the comprehensive pathogenesis of PF remains unclear due to the lack of spontaneous fibrosis mouse models. Here, we found that Ifngr1^-/-Rag2^-/- mice, lacking the mechanisms to suppress group 2 and 3 innate lymphoid cells (ILC2s and ILC3s), developed severe PF spontaneously. In Ifngr1^-/-Rag2^-/- mice, Il1rl1^hiIl13^hi-ILC2 subpopulation was increased at disease-onset phase before collagen production began. Further, defects in ILCs or IL-33, the strong ILC2 activator, prevented PF development. ILC2s directly induce collagen production by fibroblasts in vitro, and fibroblasts started to produce IL-33 in the chronic phase, presumably forming a positive feedback loop between fibroblasts and ILC2s leading to irreversible fibrosis. Moreover, the increased IL1RL1 and IL13 and decreased IFNGR1 expression levels in ILC2s from human idiopathic PF patients highlight the significance of the novel mouse model in fibrosis research.

Pemphigus vulgaris is an autoimmune blistering disease caused by IgG targeting desmoglein 3 (Dsg3), an adhesion molecule of keratinocytes. Anti-Dsg3 IgG production is prevented in healthy individuals, but it is unclear how Dsg3-specific B cells are regulated. To clarify the immunological condition regulating Dsg3-specific B cells, a pathogenic anti-Dsg3 Ig (AK23) knock-in mouse was generated. AK23 knock-in B cells developed normally without undergoing deletion or acquiring an anergic phenotype in vivo. The knock-in B cells showed Ca²⁺ influx upon IgM cross-linking and differentiated into AK23-IgG⁺ B cells after LPS and IL-4 stimulation in vitro that induced a pemphigus phenotype after adoptive transfer into Rag2^−/− mice. However, the knock-in mouse itself produced AK23-IgM but little IgG without blisters in vivo. Dsg3 immunization and skin inflammation caused AK23-IgG production and a pemphigus phenotype in vivo. Furthermore, Fcgr2b deficiency or haploinsufficiency spontaneously induced AK23-IgG production and a pemphigus phenotype with poor survival rates in AK23 knock-in mice. To assess Fcgr2b involvement in Ig class-switch efficiency, postswitch transcripts of B cells were quantified and significantly higher in Fcgr2b^−/− and Fcgr2b^+/− mice than wild-type mice in a gene dose-dependent manner. Finally, RNA sequencing revealed reduced expression of FCGR2B and FcγRIIB-related genes in patient B cells. These results indicated that Dsg3-specific B cells do not spontaneously perform pathogenic class switching in vivo, and pemphigus phenotype induction was prevented under normal conditions. Attenuated FcγRIIB signaling is also one of the drivers for pathogenic class switching and is consistent with immunological features identified from clinical samples. This study unveiled a characteristic immune state silencing autoreactive B cells in mice. Key Points Class switch did not occur in Dsg3-specific BCR knock-in mice in a steady state. Stimulation driving anti-Dsg3 IgG production induced a pemphigus phenotype in mice. Class switch–constraining immune state prevented pemphigus phenotype development.