Table 2.

Mechanisms of inducing tumor drug resistance through M2-like TAMs

	Target	Host cell	Strategy	Mechanism	Refs
Signaling pathway	PI3K/ Akt	MCF7	Tamoxifen	Activation of PI3K/Akt/mTOR signaling by TAM-secreted CCL2 promotes the TME endocrine resistance feedback loop	45
		MCF7	Tamoxifen	Activation of breast cancer cells via EGFR/PI3K/Akt signaling by feedback upregulation of SGLT1	46
	JAK/ STAT	BT549, T47D	Paclitaxel	Modulation of IL-10/STAT3/bcl-2 signaling pathway	49
		MKN45	5-FU	Secretion of CCL8 to activate JAK1/STAT3 signaling phosphorylation	50
	Jagged1/Notch	MCF7	Aromatase inhibitor	Reprogramming TAMs through high expression of the Jagged1-Notch pathway	59
	NF-κB	TFK-1	Gemcitabine	M2-like TAMs-derived tgf-β1 induces EMT and drug resistance in CCA cells via the aPKCι/NF-κB signaling pathway	63
	Hippo	GBM	ICI	Promotion of promotes M2 polarization by SOH	66
Exosome	miR-21	MFC, MGC-803	Cisplatin	Modulation of the transfer of PTEN/PI3K/Akt signaling between TAMs and cancer cells by M2-derived miR-21 via the M2-specific ApoE	81
		OVCAR3, HO-8910	Chemotherapy	M2-delivered miR-21 enhanced OCA resistance via PI3K/Akt signaling	82
	MSTRG.292666.16	H1975	Osimertinib	M2-derived MSTRG.292666.16 promoted osimertinib resistance by regulating the miR-6386-5p/MAPK8IP3 axis	83
	miR-155-5p	DLD1, HCT-8, HT-29, LoVo	5-FU	Activation of the IL-6R/STAT3/miR-204-5p signaling by miR-155-5p in TAMs through regulating C/EBPβ in CRC	84
	DLBCL-exo	OCI-LY1. OCI-LY3	Epirubicin	DLBCL-generated exosomes may promote M2 polarization through activating the GP130/STAT3 signaling pathway and highly expressing IL-10, CD206 and CD163 expression	85
	miR-588	SGC7901	Cisplatin	Stimulation of the NF-kB signaling pathway by miR-588 through partially targeting cylindromatosis in GC to prevent apoptosis	86
	MCF7-exo	MCF7/S, MCF7/DOC	Docetaxel	Exosomal delivery and the release of P-gp export the chemotherapeutic agents outside tumor cells	88
	miR-365	K989	Gemcitabine	Adoptive transfer of miR-365 in TAMs induced gemcitabine resistance	89
	miR-1246	HeyA8, Skov3ip1, A2780	Paclitaxel	miR-1246 actives P-gP by targeting Cav1/P-gP/PRPS2/M2-like macrophages signaling pathway to inhibit paclitaxel uptake and transport	90
	SOX2-OT	H1975	EGFR-TKIs	SOX2-OT, as a miRNA sponge, targeted miR-627-3p activity and upregulated Smads expression, thereby reprogramming TAMs	93
	SNHG7	H1299, SPC-A1	Docetaxel	SNHG7 induces PTEN downregulation iva recruiting CUL4A, thus stimulates the PI3K/Akt signaling pathway to induce autophagy and M2 polarization.	94
	lnc-TALC	LN229, GL261, HMC3, BV-2	Temozolomide	GBM-delivered lnc-TALC can bound to ENO1 to activate p38MAPK signaling, thus increasing C5/C5a secretion to promote M2 polarization	96
	LINC00337	MCF7,MDA-MB-231	Paclitaxel	Recruitment of M2-like TAMs by LINC00337 induces tumor development and chemoresistance	98
	HCG18	SW620	Cetuximab	Promotion of M2 polarization by HCG18 via the miR-365a-3p/FOXO1/CSF-1 axis	99
	MIR155HG	Caco2, HT29	Oxaliplatin	Acceleration of the CRC evolution by MIR155HG through modulating the miR-650/ANXA2 axis enhances oxaliplatin resistance	101
	CRNDE	MFC, SGC7901	Cisplatin	M2-delivered CRNDE inhibits PTEN ubiquitination to reduce the susceptibility of cisplatin	101
Cytokine	TNF-α	LM2	Chemotherapy	TNF-α accumulated heavily in the TME, promotes the upregulation of CXCL1 and CXCL2 through activating the NF-kβ pathway	109
		MDAMB231, 4T1, E0771	Bevacizumab	M2b TAMs promote tumor metastasis via TNF-α, and activate IDO1	110
		SMMC-7721	Anti-tumor drug	M2-like TAMs promote EMT and CSCs via the Wnt/β-catenin pathway	111
	Interleukin	HepG2, SMMC7721,	Oxaliplatin	Activation of CMA signaling pathway by M2-like TAMs via IL-17/IL-17R pathway	116
		MCF7	Doxorubicin	The polarization of M2-like TAMs enhances the IL-6 paracrine loop between TAMs and tumor cells	117
		M109, H1975, PC-9	Osimertinib	EGFR T790M-cis-L792F activated the JAK/STAT3 pathway to promote the M2 polarization	118
	Chemokine	HCT-8, HCT-116, SW620, SW480, DLD1 CT26, HT-29	ICI	Activation of p65/STAT3-CSN5-PD-L1 signaling by TAM-secreted CCL5 inhibits CD8 + T cell responses in tumor cells	122
		DLD1, HT29	5-FU	Secretion of CCL22 activates the EMT program, PI3K/Akt pathway and Caspase-mediated apoptosis	123
	IGF	SUIT2, MIA-PaCa-2	Gemcitabine	Activation of insulin/IGF1R survival signaling by M2-like TAMs or by IGF, which is modulated by M2, enhances the resistance to gemcitabine	125
TME	CCL5	DU145, PC-3	Paclitaxel, Doxorubicin	Activation of STAT3-related signaling pathway by TAM-secreted CCL5 upregulates Nanog	128
	Treg	CNE1, CNE2, 5-8 F	ICI	M2-like TAMs recruit mature Treg by secreting CCL22, CCL18 and promote the conversion of naive T cells to Treg by secreting TGF-β, IL-10	130
Proangiogenic factor	VEGF	U87-MG	Bevacizumab	Depletion of VEGF causes MIF downregulation and promotes M2 polarization	137
		LN229, U251	Temozolomide	Secretion of VEGF by hypoxic M2-like macrophages through activating the PI3K/Akt/Nrf2 pathway	138
	VEGF-A	LLC	Cyclophosphamide, Cisplatin	Secretion of VEGF-A by M2-like TAMs to promote VEGFR2 phosphorylation	139
		A549	Doxorubicin	M2-like macrophages promote VEGF-C and VEGFR3 expression thereby inhibiting p53 and PTEN expression	140
CSCs	GSC20,GSC267	GBM	ICI	secretion of GDEs to induce monocyte polarize into M2-like macrophages via STAT3 signaling	144
	CSC	Cal27	Vincristine	M2-like TAMs promote OSCC cells to produce csc-like cells and overexpress stemness-related genes	149
	GSC	GBM	Chemotherapy	M2-like macrophages promote CSCs to express stemness features by mediating PTN - PTPRZ1 paracrine signaling induction	150