In this section, we will discuss the pathological role of the STAT3 pathway and STAT6 pathway in M2-like TAM polarization, and the pharmacological effects of the agents that inhibit these pathways. Several other pathways and M2 targeting agents will be outlined at the end of this section. STAT3 is consistently active in many tumours and acts as a negative regulator for macrophage activation and the host’s inflammatory responses.[120] When the activation of STAT3 was blocked, either with a dominant negative variant or an antisense oligonucleotide, macrophages could increase

the release of IL-12 and RANTES and reverse the systemic immune tolerance.[121] Now, some STAT3 inhibitors are under investigation. For instance, a small molecular inhibitor of STAT3 (WP1066) was found to reverse immune tolerance in patients with malignant glioma, correlating with selectively Selleckchem Silmitasertib induced expressions of co-stimulatory molecules (CD80 and CD86) on peripheral macrophages and tumour-infiltrating microglias, and immune-stimulatory cytokines (e.g. IL-12).[122] Two clinical tyrosine kinase inhibitors (sunitinib and sorafenib) have shown their inhibitory

effects on STAT3 in macrophages in vitro.[123, 124] Sorafenib can restore IL-12 production but suppress IL-10 expression in prostaglandin E2 conditioned macrophages, indicating its effects on reversing the immunosuppressive cytokine profile of TAMs.[124] Moreover, two newly identified inhibitors of M2 differentiation are corosolic acid and oleanolic MLN8237 datasheet acid. They can also suppress the activation Calpain of STAT3.[125, 126] Actually, other novel STAT3 inhibitors, such as STA-21, IS3 295 and S3I-M2001, have been found to be efficient against tumours,[127] although their association with TAM re-polarization needs to

be shown. Another STAT family member important for TAM biology is STAT6. In one study, STAT6–/– mice produced predominantly M1-like tumoricidal TAMs with arginaselow and NOhigh, and > 60% of STAT6–/– mice rejected tumour metastasis.[128] Currently, at least three STAT6 inhibitors (AS1517499, leflunomide and TMC-264) have been identified. But their actions as modulators of TAMs remain to be clarified. Instead, several up-/down-stream mediators of STAT6 are more impressive because they could act as modulators of TAM function. These modulators include phosphatidylinositol 3-kinase (PI3K), Src homology 2-containing inositol-5′-phosphatase (SHIP), Krüppel-like factor 4 (KLF4) and c-Myc. PI3K positively regulates STAT6 activation in macrophages, whereas SHIP negatively regulates PI3K. Either PI3K inhibition or SHIP over-expression has been found to decrease the activity of the STAT6 pathway and to reduce M2 skewing of macrophages.[129] Therefore, the agents that are able to inhibit PI3K or stabilize SHIP activity may be therapeutic adjuvants for cancer. KLF4 is another interesting modulator protein of STAT6. Liao et al.[130] reported that the expression of KLF4 was induced in M2 macrophages and reduced in M1 macrophages.