Table 1.

An overview of the current targets, therapies or drugs and related clinical trials of immunotherapeutic strategies targeting the tumor microenvironment (TME).

Immunotherapeutic strategies targeting the TME	Classification	Targets	Therapies/Drugs	Relevant clinical trials
Therapeutic strategies based on TME inhibitory signaling	Targeting TME physical barriers	Extracellular matrix Fibroblast activating protein (FAP) Collagen Laminin (FAK)	Inhibition of Rho-kinase and FAK-mediated cell contraction (e.g., Fasudi, H1152, Defactintb) Reduction of matrix components (e.g., FAP gene-editing cells, FAP-vaccine, FAP antibody-nanoparticle, VS-4718, and PEGPH20) Inhibition of matrix cross-linking (e.g., BAPN and miRNA LOX inhibitors) and fibrosis (e.g., pirfenidone, losartan, and tranilast) Improvement of tumor vascular leakage (e.g., bevacizumab) Reduction of the effect of vascular shear stress.	IMpower 150 study LEAP-006 study (NCT03829319) LEAP-007 study (NCT03829332)
	Targeting immune checkpoints	Programmed cell death-1/PD-L1 (PD-1/PD-L1) Lymphocyte-activation gene-3 (LAG-3)T-cell immunoglobulin 3 (TIM-3) T-cell immunoglobulin and ITIM domain (TIGIT) Siglec-15(S15)	Targeting LAG-3: relatlimab (BMS-986916), LAG525 (IMP701), MK-4280, TSR-033, REGN3767, Sym022, INCAGN02385, FS118, BI754111, MGD013, and Eftilagimod alpha (Efti, IMP321, or LAG-3Ig) Targeting TIM-3: anti-TIM-3 or anti-TIM-3/PD-1/L1 bispecific antibodies Targeting TIGIT: Phase III clinical studies on advanced first-line NSCLC treatment in China include the following: MK-7684A-003 trial (PD-L1 ≥ 1%, MK-7684 + Pembrolizumab, NCT04738487), AdvanTIG-302 trial (PD-L1 ≥ 50%, BGB-A1217 + Teicilizumab, NCT04746924), and SKYSCRAPER-01 trial (high PD-L1 expression, Tiragolumab + Atenibizumab, NCT04294810).	Targeting LAG-3: phase II/III RELATIVITY-047 (CA224-047), phase III TACTI-002 trial (NCT03625323), phase II TACTI-003 study, INSIGHT-004 study; Targeting TIM-3: phase I/II clinical trials (NCT03489343, NCT03652077, NCT03099109, NCT02608268, etc.). Targeting TIGIT: phase III clinical studies: MK-7684A-003 trial, AdvanTIG-302 trial, and SKYSCRAPER-01 trial (NCT04294810).
	Targeting immunosuppressive cells	Myeloid-derived suppressor cells (MDSCs) Immunosuppressive macrophages Regulatory cells (Tregs) Tumor-associated macrophage (TAM)	Sitravatinib, an RTK inhibitor that targets TAM receptors (TYRO3, AXL, MerTK) and a variety of similar RTKs,	Phase II study (MRTX-500) Phase III SAPPHIRE study (NCT03906071) Ongoing trails: NCT02978859, NCT02219711, NCT02954991, and NCT03015740
	Targeting inhibitory cytokines	Transforming growth factor-β (TGF-β) Colony-stimulating factor-1 (CSF-1) and CSF-1 receptor (CSF-1R)	M7824 (Bintrafuspalfa), a bifunctional fusion protein targeting PD-L1 and TGF-β CSF-1R antibody: PLX3397, cabiralizumab(FPA008)	Phase Ia/Ib clinical trial (NCT02526017) Phase II clinical trial (NCT03336216)
	Targeting metabolic inhibition signaling	Solute carrier transporter (SLC) family [mainly monocarboxylate transporter (MCT)-1/4, CD36] Acyl coenzyme A cholesterol acyltransferase 1 (ACAT1) Indoleamine 2,3-dioxygenase (IDO)	Targeting MCT-1: AZD3965 CD36-antibody Targeting ACAT1: Avasimibe IDO inhibitors, IO102/IO103 (a vaccine under development that targets IDO and PD-L1)	Targeting MCT-1: clinical trial (NCT01791595) Ref. 51
Therapeutic strategies based on TME stimulatory signals	Targeting stimulatory checkpoints	CD27, CD40, OX40, glucocorticoid-induced TNF receptor (GITR), inducible co-stimulator (ICOS), and 4-1BB NKp30, NKp44, NKp46, CD226 of the natural cytotoxicity receptor (NCR) series, and FcγRIII/CD16	4-1BB targeted antibodies ADG106, LVGN6051, and PD-L1/4-1BB-bispecific antibodies ES101 and ATG-101. Monoclonal antibodies targeting FcγRIII/CD16: such as α-CD20, α-GD2, α-Her2, and α-EGFR
	Application of stimulating cytokines	IL-2/IL-2b receptor IL-12 IL-15	Bempegaldes(NKTR-214): a CD122 agonist, activating the IL-2b receptor The IL12-L19L19 fusion protein Tumor-selective oncolytic bovine poxvirus encoding IL-7 and IL-12 IL-15 superagonist, N-803,	Phase I/II PIVOT-02 study (NCT02983045) Phase II and III trials (NCT03138889 and NCT03635983, NCT02983045)
	Enhancing Antigen Presentation	Function of tumor antigens presentation	Plinabulin, a novel selective immunoregulatory microtubule binder (SIMBA) Toll-like receptor 9 (TLR9) agonists: SD-101, CMP-001 Oncolytic viruses (OVs) and modified OVs: BiTE-integrated OVs, in situ OVs (showing adenovirus-mediated herpes simplex virus thymidine kinase expression) Therapeutic tumor vaccines: Sipuleucel-T, OSE-2101, PVX-410 vaccine, folate receptor α vaccine, and neoantigen vaccine	Phase III study DUBLIN-3 (NCT02504489, ESMO2021, LBA48) I-SPY2 study (NCT01042379) Phase II study (NCT03004183) Phase III Atalante-1 study Ongoing clinical trials NCT02680184, NCT03362060, NCT02826434, NCT03012100, NCT03199040, and NCT03606967.
	Application of immune effector cells	Hematologic targets (e.g., CD19, CD20, and CD138) Solid tumors (e.g., HER2, GD2, PSCA, and EGFRvIII) Immune cells	CAR-T cells, CT041 targeting the gastro-specific membrane protein CLDN18.2, CD19-CAR-T cells, CAR-T cell therapy triggered by Amph-ligands CAR-NK cells, anti-CD19 IL-15-secreting CAR-NK cells CAR (targeting HER2)-macrophages (Macs) CAR-expressing iPSC-derived macrophages (CAR-iMac) TILs: lifileucel (LN-144), ITIL-168, LN-145 and LN-145-S1	Phase II C-144-01 study Phase II study on LN-145 (NCT04111510) Phase II InnovaTIL-01 study IOV-COM-202 (NCT03645928)