Abstract
A high infiltration of tumor-associated macrophages (TAMs) in hepatocellular carcinoma (HCC) is associated with a negative prognosis for patients. Kupffer cells (KCs) constitute a stationary tissue-resident macrophage subset of the liver, playing a pivotal role in maintaining homeostasis. The increased expression of tubulin beta-3 chain (TUBB3) is associated with the aggressiveness of various epithelial tumors. In this study, we investigate the role of TUBB3 in TAM of HCC and explore the mechanisms. TUBB3 is significantly augmented in HCC tissues, and the knockdown of TUBB3 in Kupffer cells (KCs) inhibits M2 polarization of TAM and hinders the HCC progression. In addition, TUBB3 knockdown enhances the efficacy of PD-1 immunotherapy in vivo. TUBB3 inhibits phosphatase and tensin homolog (PTEN)-induced serine-threonine protein kinase (AKT) phosphorylation, and activation of the AKT signaling reverses the inhibition of TAM-M2 polarization by knockdown of TUBB3 and promotes the malignant behavior of HCC cells. Deltex1 (DTX1) promotes TUBB3 ubiquitination, inducing the degradation of TUBB3. DTX1 overexpression suppresses the M2 polarization of TAM, which is overturned by TUBB3 overexpression. These findings provide the first evidence indicating that DTX1 mediates the ubiquitination of TUBB3 in KCs to block the AKT signaling and the M2 polarization of TAM in HCC.