Immunosuppressive tumor microenvironment shape pancreatic cancer unresponsive to current immunotherapies

Table 1 Therapeutic strategies targeting immunosuppressive cells in pancreatic ductal adenocarcinoma

Target	Strategy	Core mechanism	Example agents
Tregs	Depletion	Anti-CD25 depletion	Basiliximab mogamulizumab
		Anti-CCR4 blockade
	Functional inhibition	TGF-β pathway blockade	Galunisertib oleclumab/ciforadenant
		Adenosine axis blockade
	Reprogramming	Selective IL-2Rβγ activation	Bempegaldesleukin THOR-707
MDSCs	Block recruitment	CCR2 inhibition	PF-04136309 plerixafor/BL-8040
		CXCR4 inhibition
	Induce differentiation	Retinoic acid-induced maturation	ATRA
	Selective depletion	Cytotoxic targeting of proliferating cells	Gemcitabine
TAMs	Depletion	CSF1R signaling inhibition	Pexidartinib
	Repolarization	CD40 activation	Sotigalimab motolimod eganelisib
		TLR activation
		PI3Kγ inhibition

TGF-β: Transforming growth factor β; IL: Interleukin; Treg: Regulatory T cells; TAM: Tumor-associated macrophages; MDSCs: Myeloid-derived suppressor cells; CCR4: C-C motif chemokine receptor 4; CCR2: C-C motif chemokine receptor 2; CSF1R: Colony-stimulating factor 1 receptor; TLR: Toll-like receptor; PI3Kγ: Phosphoinositide 3-kinase γ; ATRA: All-trans retinoic acid.

Table 2 Selected landmark clinical trials targeting the immunosuppressive microenvironment in pancreatic ductal adenocarcinoma

Drug	Trial name	NCT number	Strategy	Phase	Combination
Motixafortide	COMBAT	NCT02826486	CXCR4 inhibitor	Phase IIa	+ Pembrolizumab ± chemo
			Disrupt CXCL12 barrier
			Reduce MDSCs
Plerixafor	-	NCT04543071	CXCR4 inhibitor	Phase II	+ PD-1 blockade
Cemiplimab			Enhance TILs
ATRA	STARPAC	NCT03307148	Induce MDSC differentiation	Phase I	+ Gemcitabine/nab-paclitaxel
Gemcitabine	MPACT/APACT	NCT01746979	Low-dose chemo	Phase III	Doublet chemo
Nab-paclitaxel			Deplete MDSCs/Tregs
Selicrelumab	-	NCT02588443	TAM repolarization	Phase I	Monotherapy
			APC activation
Sotigalimab	PRINCE	NCT03214250	CD40 agonist	Phase II	+ Gem/nab-pac ± nivolumab
Mitazalimab	OPTIMIZE-1	NCT04888312	CD40 agonist	Phase Ib/II	+ mFOLFIRINOX

NCT: National clinical trial; CXCR4: C-X-C motif chemokine receptor 4; CXCL12: C-X-C motif chemokine ligand 12; TILs: Tumor-infiltrating lymphocytes; ATRA: All-trans retinoic acid; PD-1: Programmed cell death protein 1; MDSC: Myeloid-derived suppressor cell; Tregs: Regulatory T cells; TAM: Tumor-associated macrophage; APC: Antigen-presenting cell.