ADPGK‐AS1 long noncoding RNA switches macrophage metabolic and phenotypic state to promote lung cancer growth

Long noncoding RNAs (lncRNAs) influence the transcription of gene networks in many cell types, but their role in tumor‐associated macrophages (TAMs) is still largely unknown. We found that the lncRNA ADPGK‐AS1 was substantially upregulated in artificially induced M2‐like human macrophages, macrophages exposed to lung cancer cells in vitro , and TAMs from human lung cancer tissue. ADPGK‐AS1 is partly located within mitochondria and binds to the mitochondrial ribosomal protein MRPL35. Overexpression of ADPGK‐AS1 in macrophages upregulates the tricarboxylic acid cycle and promotes mitochondrial fission, suggesting a phenotypic switch toward an M2‐like, tumor‐promoting cytokine release profile. Macrophage‐specific knockdown of ADPGK‐AS1 induces a metabolic and phenotypic switch (as judged by cytokine profile and production of reactive oxygen species) to a pro‐inflammatory tumor‐suppressive M1‐like state, inhibiting lung tumor growth in vitro in tumor cell‐macrophage cocultures, ex vivo in human tumor precision‐cut lung slices, and in vivo in mice. Silencing ADPGK‐AS1 in TAMs may thus offer a novel therapeutic strategy for lung cancer. Synopsis Whether gene network‐controlling long noncoding RNAs also affect tumor‐associated macrophages (TAMs) is unclear. Here, the lncRNA ADPGK‐AS1 is found to be upregulated in TAMs and to drive a tumor‐promoting M2‐like phenotype associated with lung cancer growth. RNA sequencing of the artificially induced M2‐phenotype of human macrophages shows upregulated lncRNA ADPGK‐AS1 expression. ADPGK‐AS1 is expressed/located in macrophage mitochondria and interacts with the mitochondrial ribosomal protein, MRPL35. MRPL35 is highly expressed in M2‐like TAMs and is associated with poor survival in lung cancer patients. Macrophage overexpression of ADPGK‐AS1 increases mitochondrial number and fission and stimulates the tricarboxylic acid cycle, suggesting an M2‐like phenotype. TAMs with high ADPGK‐AS1 expression promote lung tumor growth, while TAMs with little expression suppress it. Graphical Abstract Expression of the long noncoding RNA ADPGK‐AS1 results in a phenotypic switch to the tumor‐promoting M2‐like identity in human macrophages.