Tumor-Secreted Lipids Induce ER Stress Response to Polarize Macrophages

Within the tumor microenvironment, macrophages can be reprogrammed to support tumor growth, but mechanisms by which tumor cells induce tumor-associated macrophage (TAM) polarization are not completely known. Given studies suggesting that deregulated lipid metabolism in cancer cells can affect immune populations to enhance tumor progression, Di Conza and colleagues investigated whether altered lipid metabolism could contribute to protumorigenic TAM polarization. In murine models of melanoma, TAMs displayed increased lipid content compared with splenic macrophages. Supporting the role of a tumor-derived factor, treatment of bone marrow–derived macrophages with tumor cell–derived conditioned media (CM) similarly increased lipid content, while also enhancing expression of protumorigenic polarization markers including Arg1 and Mrc1. Swollen endoplasmic reticulum (ER) morphology prompted an assessment of ER stress, revealing that TAMs specifically activated an XBP1-mediated response downstream of ER stress sensor IRE1. Small-molecule inhibition of IRE1 in CM-treated macrophages decreased lipid accumulation and levels of spliced XBP1, hindering polarization. Correspondingly, macrophage-specific ablation of Xbp1 decreased TAM polarization and slowed tumor growth. However, Xbp1 overexpression alone was not sufficient to induce polarization, leading to consideration of the additional role of signaling molecule STAT3 which was previously shown to promote tumor growth by modulating TAMs. Indeed, CM treatment induced STAT3 phosphorylation in an IRE1-dependent manner to polarize protumorigenic TAMs, in parallel with the IRE1–XBP1 axis. Mechanistically, the IRE-mediated ER stress response was triggered by altered lipid metabolism in tumor cells, resulting in enhanced TAM uptake of tumor-secreted ß-glucosylceramide. Within TAMs, ß-glucosylceramide activated the pattern recognition receptor Mincle (also known as CLEC4E), enhancing cholesterol synthesis and shifting the lipid composition of the ER membrane. Rescuing lipid imbalance with an liver X receptor agonist to enhance expression of the enzyme Lpcat3, known to restrict lipid overloading–induced ER stress, reduced polarization and inhibited tumor growth. In summary, this work reveals a mechanism in which tumor-secreted lipids promote macrophage polarization and antitumor immunity by reshuffling lipid composition in the ER membrane.

Di Conza G, Tsai C-H, Gallart-Ayala H, Yu Y-R, Franco F, Zaffalon L, et al. Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity. Nat Immunol 2021;22:1403–15.

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