TABLE 4.

The potential therapeutic strategies to overcome surgical trauma related cancer progression

Therapeutic strategies	Targets	Drugs	Mechanisms	References
Anti‐inflammation	NSAIDs	Aspirin, corticosteroids	Inhibit formation of fibrin and platelet clots	146, 147, 148, 149
	COXIBs	Celecoxib, Parecoxib	Exhibits relative selectivity for COX‐2 over COX‐1	145, 150, 151, 152
	IFN‐α	Infliximab	Activated the host immune response	153
	IL‐6	Siltuximab	Blocking the IL‐6–induced expression of proteins responsible for acute inflammation	154
DAMPs	Cell‐free DNA clearance	Nucleic acid scavenging microfiber meshes	Reduce the nuclei DNA induced inflammation	129
	Complement therapeutics	C1 esterase, C5a	Reduce tissue inflammation without blocking the complement cascade systemically	130, 131, 132
	HBMG‐1	Glycyrrhizin	Reverse and prevent activation of innate immunity and significantly attenuate damage in models of sterile‐induced threat	. 127 , 128
	TLR2	OPN‐305	Blocks the activation of TLR 2‐mediated innate immunity signaling	. 136
	TLR4	MD2 inhibition (GLA‐SE)	Promotes strong Th1 and balanced IgG1/IgG2 responses to protein vaccine antigens	137
	TLR9	CpG‐C oligodeoxynucleotides	Senses CpG DNA in endosomes and induces the IFN response	133
		CMP‐001		134
	RAGE	FPS‐ZM1	Blocks the binding of amyloid β (Aβ) protein to RAGE and inhibits Aβ40‐ and Aβ42‐induced cellular stress in RAGE‐expressing cells	135
	NF‐κB	BAY11‐7082	Suppress NF‐κB activation and reducing the production of chemokines	140
	IL‐1β	Anakinra	Reduce the secretion of CCL2, CCL5, and CXCL5	110
	NLRP3	MCC950, CY‐09, OLT1177, Tranilast, and Oridonin	Directly target NLRP3 to downregulate the inflammatory and pyroptosis signal	139
Immunotherapy	Anti‐PD‐1	Pembrolizumab	Ameliorated T‐cell proliferation and partially reversed the T‐cell apoptosis induced by surgical trauma	124, 161
	Adoptive cell transfer	NKTT	Supplement the reduced number of NK cells after surgical stress	160
	Replicating viruses	Oncolytic viruses	Engage and mature conventional dendritic cells, which in turn activate NK‐ and T‐cells	157
	Prestimulation of immunity	Influenza vaccine	Administration 1 day before surgery, enhancing NK‐cell function through IFN‐α	158, 159
Neutrophil‐based therapy	Anti‐NET	DNAse I	Eliminating the NETs that format under surgical stress	166
	CXCR2	AZD5069, MK‐7123	Block the chemotaxis of neutrophil in acute inflammation	164
Macrophage‐based therapy	Minor groove of DNA Caspase 8	Trabectedin	Reducing the number of TAMs and the production of inflammatory cytokines and chemokines	182, 183, 184
	CSF‐1R	RG7155	Reduce the recruitment of macrophage and induced the apoptosis of activated macrophage	171
	TAM (TYRO3, AXL, MER)	RXDX‐106	Increased intratumoral CD8+ T cells and T cell function as indicated by both IFN‐γ production and LCK phosphorylation	185
	CD40	CP‐870,893	Reprogrammed TAMs create a proinflammatory environment that elicits effective T cell responses	172, 173, 174
	TLR9	IMO‐2055	Reprogramming protumoral macrophage to tumoricidal macrophage	175, 176, 177
	TLR7	Imiquimod	Phenotypic switch of TAMs to tumoricidal macrophages	178, 179, 180
	CD47	Hu5F9‐G4	A humanized, IgG4 isotype, CD47‐blocking monoclonal antibody, enables killing and phagocytosis of tumor cells by macrophages	181
	CCR2	PF04136309	Reduced the activated macrophage recruitment and regulated inflammation in wound healing	170
	CCL2	Carlumab	CCL2 increased after surgical wound, reduced the activated macrophage recruitment	167, 168, 169
MDSCs	Epigenetic therapy	5‐Azacytidine and entinostat	Downregulation of CCR2 and CXCR2 and promote MDSC differentiation into a more‐interstitial macrophage‐like phenotype	186
	PDE‐5	Sildenafil, Tadalafil	Downregulating ARG1 and nitric oxide expression	187, 188
	CXCR1/2	Reparixin, MK7123	Inhibit CXCR2+ G‐MDSC trafficking	190, 191
	ATRA	‐	Vitamin A derivative with antiproliferative properties	193, 194
	Vitamin D3	‐	Induce myeloid cell differentiation and enhance antitumor activity	195
	Gemcitabine/5‐FU	‐	Eliminate MDSC through induction of apoptosis	196
Treg based therapy	CD25	Daclizumab	Deplete CD4+CD25+ Treg cells and subsequently reduced Treg cell‐ mediated suppression of effector T cell function	206, 207
	CCR4	Mogamulizumab	Augmented the induction of cancer‐testis antigen (NY‐ ESO‐1)‐specific CD4+ and CD8+ T cells	208, 209, 210
	GITR	MEDI1873	Activation of antigen‐specific CD4+ effector T cells and selective depletion of Treg cells	211
	PI3Kδ	Parsaclisib	Treg cell maintenance and function are dependent on PI3Kδ signaling and inactivation of PI3Kδ in Treg cells resulted in increased activity of CD8+ T cells	212, 213
Antiangiogenesis	Monoantibody	Bevacizumab	A recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human VEGF	204
	Endostatin	Endostar	As postoperative complementary chemotherapy, due to the decrease of endostatin after surgery	203