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The Dja2 knockout (Dja2−/−) mice had respiratory distress, and >60% died within 2 days after birth. The surviving adult Dja2−/− mice were infertile and the lungs of Dja2−/− mice showed several abnormalities, including the processing defect of prosurfactant protein C in the alveolar epithelial type II cells and the accumulation of glycolipids in enlarged alveolar macrophages. The luminal pH of acidic organelles in Dja2−/− cells was shifted to pH 5.37–5.45. This deviated pH was immediately restored to control levels (pH 4.56–4.65) by the addition of a diuretic, ethyl isopropyl amiloride (EIPA). Although the role of DJA2 in maintaining the pH homeostasis of lysosome‐related organelles is currently obscure, this rapid and remarkable pH resilience is best explained by an EIPA‐sensitive proton efflux machinery that is disorganized and overactivated due to the loss of Dja2. [ABSTRACT FROM AUTHOR]

Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, mechanisms underlying resistance to ICI therapy, including impaired T cell infiltration, low immunogenicity, and tumor "immunophenotypes" governed by the host, remain unclear. We previously reported that in some cancer contexts, tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) has tumor-promoting functions. Here, we asked whether ANGPTL2 deficiency could enhance antitumor ICI activity in two inflammatory contexts: a murine syngeneic model of colorectal cancer and a mouse model of high-fat diet (HFD)-induced obesity. Systemic ANGPTL2 deficiency potentiated ICI efficacy in the syngeneic model, supporting an immunosuppressive role for host ANGPTL2. Relevant to the mechanism, we found that ANGPTL2 induces pro-inflammatory cytokine production in adipose tissues, driving generation of myeloid-derived suppressor cells (MDSCs) in bone marrow and contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy. Moreover, HFD-induced obese mice showed impaired responsiveness to ICI treatment, suggesting that obesity-induced chronic inflammation facilitated by high ANGPTL2 expression blocks ICI antitumor effects. Our findings overall provide novel insight into protumor ANGPTL2 functions and illustrate the essential role of the host system in ICI responsiveness., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)