Cancers rely on the tumor microenvironment, which comprises a variety of nonmalignant stromal cells for growth, invasion, and metastasis.¹ x 1 Zhou, S.L., Dai, Z., Zhou, Z.J. et al. CXCL5 contributes to tumor metastasis and recurrence of intrahepatic cholangiocarcinoma by recruiting infiltrative intratumoral neutrophils. Carcinogenesis. 2014; 35: 597–605 Crossref | PubMed | Scopus (40) | Google Scholar See all References ^{, 2} x 2 Quail, D.F. and Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013; 19: 1423–1437 Crossref | PubMed | Scopus (1358) | Google Scholar See all References Recent evidence has indicated that there is a complex and multidirectional interplay between tumor cells and immune or nonimmune stromal cells during cancer development and progression. The interaction between tumor and stromal cells may polarize stromal cells to favor tumor promotion.² x 2 Quail, D.F. and Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013; 19: 1423–1437 Crossref | PubMed | Scopus (1358) | Google Scholar See all References ^{, 3} x 3 Brandau, S., Dumitru, C.A., and Lang, S. Protumor and antitumor functions of neutrophil granulocytes. Semin Immunopathol. 2013; 35: 163–176 Crossref | PubMed | Scopus (63) | Google Scholar See all References Moreover, unlike tumor cells, stromal cells within the tumor microenvironment are genetically stable and represent an attractive therapeutic target because they are less likely to develop drug resistance.² x 2 Quail, D.F. and Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013; 19: 1423–1437 Crossref | PubMed | Scopus (1358) | Google Scholar See all References

Sorafenib, a potent multikinase inhibitor, has been recognized as the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). However, the direct functional mechanism of tumor lethality mediated by sorafenib remains to be fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, we showed sorafenib induced both apoptosis and autophagy in human HCC cells through a mechanism that involved endoplasmic reticulum (ER) stress and was independent of the MEK1/2-ERK1/2 pathway. Upregulation of IRE1 signals from sorafenib-induced ER stress was critical for the induction of autophagy. Moreover, autophagy activation alleviated the ER stress-induced cell death. Inhibition of autophagy using either pharmacological inhibitors or essential autophagy gene knockdown enhanced cell death in sorafenib treated HCC cell lines. Critically, the combination of sorafenib with the autophagy inhibitor chloroquine produced more pronounced tumor suppression in HCC both in vivo and in vitro. These findings indicated that both ER stress and autophagy were involved in the cell death evoked by sorafenib in HCC cells. The combination of autophagy modulation and molecular targeted therapy is a promising therapeutic strategy in treatment of HCC.

Metastasis is one of the main causes of poor prognosis for hepatocellular carcinoma (HCC), which has been linked to cell-death resistance. Autophagy is an important survival mechanism under conditions of cell stress. We hypothesized that autophagy may play a role in HCC metastasis due to its prosurvival effect. Highly metastatic HCC cell lines with stable autophagy inhibition were established via lentivirus-mediated silencing of BECN1 and ATG5 genes. Mouse models of pulmonary metastasis were then developed using the cells with or without autophagy inhibition. The analysis of lung metastasis by histopathological examination and small animal imaging showed that autophagy inhibition significantly decreased the incidence of pulmonary metastases in vivo. Further invasion, migration, detachment, lung colonization, and epithelial-mesenchymal transition (EMT) assays indicated that autophagy inhibition did not affect cell invasiveness, migration or EMT but attenuated the anoikis-resistance and lung colonization of HCC cells. Investigation of the molecular mechanisms underlying showed that the autophagy-inhibition-mediated anoikis-resistance attenuation was associated with the regulation of apoptotic signaling. As autophagy inhibition was shown to be able to suppress HCC metastasis, an autophagy-based HCC tissue-specific target therapy system (AFP-Cre/LoxP-shRNA) was constructed. In vitro and in vivo analyses showed that the system was able to efficiently inhibit autophagy of HCC cells and tissue in a tissue-specific manner. Further in vivo metastasis assay showed that intratumoral administration of the system could significantly suppress lung metastasis. Together, our findings suggest that autophagy may be involved in HCC metastasis through facilitating anoikis resistance and lung colonization of HCC cells. Autophagy-based HCC tissue-specific target therapy may be a new strategy for the management of HCC metastasis.

Background: The Th17 subset and IL-17 have been found in increased frequencies within certain tumors. However, their relevance in cancer biology remains controversial. This study aimed to clarify the biological action of IL-17 on hepatocellular carcinoma (HCC). Methods: Effects and underlying molecular mechanisms of IL-17 on human HCC were explored in vitro using exogenous IL-17 stimulation and in nude mice by implanting IL-17 overexpressed HCC cells. The clinical significance of IL-17 was investigated in tissue microarrays containing HCC tissues from 323 patients following hepatectomy using immunohistochemistry. Results: Although exogenous IL-17 showed no direct effect on the growth rate of HCC cells in vitro, PCR and ELISA showed that IL-17 selectively augmented the secretion of diverse proinvasive factors and transwell showed a direct promotion of invasion of HCC cells by IL-17. Furthermore, transfection of IL-17 into HCC cells significantly promoted neoangiogenesis, neutrophil recruitment and tumor growth in vivo. Using siRNA mediated knockdown of AKT and STAT3, we suggested that the effects of IL-17 were operated through activation of the AKT signaling in HCC, which resulted in IL-6 production. Then, IL-6 in turn activated JAK2/STAT3 signaling and subsequently up-regulated its downstream targets IL-8, MMP2, and VEGF. Supporting these findings, in human HCC tissues, immunostaining indicated that IL-17 expression was significantly and positively associated with STAT3 phosphorylation, neutrophil infiltration and increased tumor vascularity. The clinical significance of IL-17 was authenticated by revealing that the combination of intratumoral IL-17+ cells and phospho-STAT3 served as a better prognosticator for postoperative tumor recurrence than either marker alone. Conclusions: IL-17 mediated tumor-promoting role involves a direct effect on HCC cells through IL-6/JAK2/STAT3 induction by activating the AKT pathway.

Background: The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma (HCC) remains poor. Although serine‐ and arginine‐rich splicing factor (SRSF) family members play crucial roles in tumors, their impact on tumor immunology remains unclear. This study aimed to elucidate the role of SRSF10 in HCC immunotherapy. Methods: To identify the key genes associated with immunotherapy resistance, we conducted single‐nuclear RNA sequencing, multiplex immunofluorescence, and The Cancer Genome Atlas and Gene Expression Omnibus database analyses. We investigated the biological functions of SRSF10 in immune evasion using in vitro co‐culture systems, flow cytometry, various tumor‐bearing mouse models, and patient‐derived organotypic tumor spheroids. Results: SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8 ⁺ T cell activity. Mechanistically, SRSF10 interacted with the 3′‐untranslated region of MYB , enhancing MYB RNA stability, and subsequently upregulating key glycolysis‐related enzymes including glucose transporter 1 ( GLUT1 ), hexokinase 1 ( HK1 ), lactate dehydrogenase A ( LDHA ), resulting in elevated intracellular and extracellular lactate levels. Lactate accumulation induced histone lactylation, which further upregulated SRSF10 expression. Additionally, lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages, thereby activating transcription and enhancing pro‐tumor macrophage activity. M2 macrophages, in turn, inhibited the enrichment of CD8 ⁺ T cells and the proportion of interferon‐γ ⁺ CD8 ⁺ T cells in the tumor microenvironment (TME), thus creating an immunosuppressive TME. Clinically, SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1 (PD‐1) monoclonal antibodies (mAbs) in both murine and human preclinical models. Conclusions: The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti‐PD‐1 resistance. Inhibiting SRSF10 by 1C8 may overcome anti‐PD‐1 tolerance in HCC.