Immunotherapy in liver metastases: Challenges, emerging evidence, and future directions

Table 3 Key clinical and translational studies testing combination strategies to enhance immunotherapy in liver metastases

Strategy	Mechanistic target	Representative trial/evidence	Primary cancer(s)	Outcome summary	Clinical implication
VEGF blockade + ICI[137,138]	Vascular normalization, myeloid suppression	IMpower150 (ABCP regimen)	NSCLC (with liver mets)	OS: HR = 0.68; improved immune infiltration	Supports VEGF + PD-L1 combination
Dual checkpoint blockade[92]	T-cell priming & exhaustion	CheckMate 9 LA	NSCLC, melanoma, CRC	Higher ORR & PFS in liver mets	Increased efficacy but higher toxicity
TGF-β + PD-L1 blockade[158-160]	Fibrosis reversal, stromal remodeling	Bintrafusp alfa trials	Mixed metastatic	Disease control approximately 10%-15%	Promising mechanism; modest efficacy
CSF1R/CCR2 blockade + PD-1[162]	Myeloid reprogramming	Ongoing phase I/II	CRC, NSCLC	Preclinical synergy with PD-1	Pending translation
Epigenetic modulation + ICI[163]	Antigen presentation, viral mimicry	Early-phase trials	Multiple cancers	MHC expression & T-cell infiltration increase	Converts cold to hot lesions
Adoptive cell therapy[166]	Enhanced intrahepatic trafficking	Hepatic artery CAR-T delivery	CRC, HCC	Feasible; improved local homing	Useful for liver-limited disease

ICI: Immune checkpoint inhibitor; VEGF: Vascular endothelial growth factor; PD-1: Programmed cell death 1; PD-L1: Programmed death ligand-1; NSCLC: Non-small cell lung cancer; CRC: Colorectal cancer; OS: Overall survival; PFS: Progression free survival; ORR: Objective response rate; CAR-T: Chimeric antigen receptor-T; HCC: Hepatocellular carcinoma; TGF-β: Transforming growth factor-beta.