TABLE 1.

Landmark and ongoing trials of targeting tumor immune microenvironment synergize ICIs.

Treatment type	Treatment mechanism	Trial name (NCT number)	Current status
CTLs-based therapy with ICIs	Blockade of inhibitory checkpoints: Anti-PD-1/Anti-PD-L1/Anti-CTLA-4/Other ICIs, enabling tumor-reactive T cells to overcome regulatory inhibitory mechanisms.	NCT02453594/NCT00094653/NCT01927419 NCT01721746/NCT02108652/NCT02125461	Combination therapies to overcome tumor immune evasion, other ICIs have emerged as potential targets.
NK cells -based therapy with ICIs	1. Targeting NK inhibitory molecules 2. Targeting NK cell activating signals 3. Adoptive NK cells therapy	NCT02665650/NCT03586869/NCT04261439 NCT03387085/NCT04143711/NCT03841110	Natural killer (NK) cell-based therapies are emerging as safe and effective treatments for some cancers, auxiliary methods for enhancing the therapeutic activity of NK cells include immune- checkpoint inhibitors
TAMs-targeted therapy with ICIs	1. Anti-CSF-1 antibodies and CSF-1R inhibition to deplete macrophages 2. Agonistic anti-CD40 or inhibitory anti-CD47 antibodies to stimulate macrophages 3. Modulation of macrophage phenotype 4. Eliminating TAMs already present in the TME 5. Inhibition of monocyte recruitment 6. Reprogramming of TAMs	NCT04123379/NCT03767582/NCT03059147 NCT02826486/NCT02907099/NCT04058145 NCT02777710/NCT02323191/NCT03768531 NCT02554812/NCT03558139/NCT03869190 NCT02807844/NCT02890368/NCT02663518 NCT01103635/NCT03123783/NCT02304393 NCT04116320/NCT03435640/NCT04193293	To convert its immunosuppressive ability to its potential immunostimulatory function, which is beneficial to the current ICI-based immunotherapy
MDSC-targeted therapy with ICIs	1. Decrease MDSCs recruitment 2. Promote MDSC depletion 3. Reprogram MDSCs to enhance anti-tumor immunity	NCT03214666/NCT02403778	Combined treatment with ICIs along with small molecule inhibitors to precise target MDSC remains challenge.
Neutrophils-targeted therapy with ICIs	Inhibition of various chemokines(IL8, Arg1, CXCR2, IL1β)to retard PMN recruitment and function.	NCT03161431/NCT03184870/NCT03473925 /NCT04123379/NCT02903914/NCT03631199	Pre-clinical studies by targeting neutrophil recruitment and neutrophil immunosuppressive function are currently under to complement the ICIs monotherapy
Tregs-targeted therapy with ICIs	Depletion of Tregs synergizes with ICIs to eradicate established tumors, for example blocking CCR4 and Tregs chemotaxis; blocking various chemokines and chemokine receptor (TGF-β, IL-10 and IL-35)	NCT02476123/NCT02705105/NCT02444793/NCT02301130/NCT02503774	Through depleting Tregs depletion combination with ICIs, eliminating Tregs mediated resistance
Stroma–targeted therapy/anti-angiogenesis with ICIs	Stroma–targeted therapy by reversing CAFs and ECM to antitumorigenic roles. By normalizing vessel formation, reducing negative regulatory components like Tregs, promoting of CTL infiltration and activation	NCT02681549/NCT02337491/NCT02348008 NCT03475004/NCT02443324/NCT03650764 NCT02210117/NCT02873962/NCT03452579 NCT02999295/NCT03502746/NCT02336165	Potential stromal targeting cancer therapies are underway. ICIs coupling with anti-angiogenesis have already shown efficacy in the clinic, but deeper understanding of the immunomodulatory capacity still unsatisfactory