Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity

Abstract

Tumor-associated macrophages (TAMs) display pro-tumorigenic phenotypes for supporting tumor progression in response to microenvironmental cues imposed by tumor and stromal cells. However, the underlying mechanisms by which tumor cells instruct TAM behavior remain elusive. Here we uncover that tumor cell-derived glucosylceramide stimulated unconventional endoplasmic reticulum (ER) stress responses by inducing reshuffling of lipid composition and saturation on the ER membrane in macrophages, which induced IRE1-mediated spliced XBP1 production and STAT3 activation. The cooperation of spliced XBP1 and STAT3 reinforced the pro-tumorigenic phenotype and expression of immunosuppressive genes. Ablation of XBP-1 expression with genetic manipulation or ameliorating ER stress responses by facilitating LPCAT3-mediated incorporation of unsaturated lipids to the phosphatidylcholine hampered pro-tumorigenic phenotype and survival in TAMs. Together, our findings reveal the unexpected roles of tumor cell-produced lipids that simultaneously orchestrate macrophage polarization and survival in tumors via induction of ER stress responses and therapeutic targets for sustaining host anti-tumor immunity.

STAT3 pathway in cancers: Past, present, and future

“… 137 IL‐6‐dependent STAT3 activation induces M2 polarization while inhibiting M1 activation, and this promotes cancer progression and reduces patient survival. 138 , 139 , 140 Besides inducing M2 polarization, the STAT3 pathway also upregulates PD‐L1 expression in cancer cells induced by TAMs. Zhang et al.…”

“…137 IL-6-dependent STAT3 activation induces M2 polarization while inhibiting M1 activation, and this promotes cancer progression and reduces patient survival. [138][139][140] Besides inducing M2 polarization, the STAT3 pathway also upregulates PD-L1 expression in cancer cells induced by TAMs. Zhang et al conducted a study to demonstrate how TAMs suppress immune activation and promote the invasive capacity of cancer cells via the STAT3 pathway.…”

Research progress in the role and mechanism of LPCAT3 in metabolic related diseases and cancer

“…Expression of XBP1 drives TAM in a pro-tumourigenic direction, thus providing a survival advantage to the tumour. Genetic ablation of Xbp1 in mouse bone marrow cells inhibited tumour growth and was accompanied by a significant loss of TME macrophages 87 . IRE1 contains a transmembrane structural domain that senses lipid imbalance and induces its dimerisation and activation 88 and increased cholesterol accumulation may realign the lipid composition of ER membranes, resulting in a lower ratio of phosphatidylcholine to phosphatidylethanolamine (PC/PE ratio).…”

“…LPCAT3 overexpression decreased the PC/PE ratio and unsaturated PC abundance on ER membranes in YUMM1.7 tumor cell-derived conditioned medium (CM) treated bone marrow (BM)-derived macrophages (BMDM). More importantly, LXR-mediated induction of macrophage LPCAT3 can be used to reawaken the anti-tumour response 87 .…”

The expanding role of lyso-phosphatidylcholine acyltransferase-3 (LPCAT3), a phospholipid remodeling enzyme, in health and disease

“…Nevertheless, the involvement of LPCAT3 in the processes of cell death and oncogenesis calls for caution regarding the potential deleterious effects of such modulators (Fig. 3) [11,24,26 ▪ ].…”