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

Table 1 Liver-resident cells and their roles in metastatic colonization and immune suppression

Cell type	Key functions in liver metastasis	Roles in metastatic colonization & immune suppression
KCs[39-46]	Liver-resident macrophages that are the first immune cells to contact CTCs in hepatic sinusoids	Can exert early tumoricidal activity but may become reprogrammed into an immunosuppressive phenotype promoting T-cell exhaustion and MDSC accumulation
LSECs[13-16,47-49]	Fenestrated endothelial cells regulating leukocyte trafficking, antigen presentation, and vascular tone	Under pathological activation, LSECs upregulate adhesion molecules and promote tumor cell arrest, transmigration, and angiogenesis
HSCs[50-55,109]	Perisinusoidal cells that can transition into myofibroblast-like CAFs and remodel ECM	Activated by tumor-derived factors to secrete IL-8, deposit collagen, and create a fibrotic, immune-excluded microenvironment
Hepatocytes[56-61]	Primary parenchymal liver cells central to metabolism and paracrine signaling	Modulate Fas/FasL, IGF2, HGF, and FGL1 to support tumor survival, proliferation, and suppression of CD8+ T-cell and NK-cell responses

KC: Kupffer cell; CTC: Circulating tumor cell; MDSC: Myeloid-derived suppressor cell; LSEC: Liver sinusoidal endothelial cell; HSC: Hepatic stellate cell; CAF: Cancer-associated fibroblast; ECM: Extracellular matrix; IL: Interleukin; FasL: Fas ligand; IGF2: Insulin-like growth factor 2; HGF: Hepatocyte growth factor; FGL1: Fibrinogen-like protein 1; NK: Natural killer.

Table 2 Clinical evidence summary of immune checkpoint inhibitor outcomes in liver metastases

Tumor type	Analysis	Treatment/comparison	Endpoint	Liver metastasis subgroup result	Overall population result (for comparison)	Key finding regarding liver metastases
Pan-cancer[77]	Meta-analysis	ICI-treated patients (vs without liver mets)	OS, PFS	OS: HR = 1.82, 95%CI: 1.59-2.08; PFS: HR = 1.68, 95%CI: 1.49-1.89	N/A	Liver metastases associated with significantly worse OS and PFS
Pan-cancer[78]	Pan-cancer analysis	ICI monotherapy	OS	10 months	20 months (patients without liver disease)	Markedly shorter OS for those with liver metastases
NSCLC[81]	Meta-analysis	ICIs vs control	PFS, OS	PFS: HR = 0.64, 95%CI: 0.55-0.75; OS: HR = 0.82, 95%CI: 0.72-0.94	PFS: HR = 0.56, 95%CI: 0.50-0.63; OS: HR = 0.73, 95%CI: 0.66-0.81	Benefit is present but attenuated compared to those without liver mets (larger HR values)
NSCLC[82]	Pooled CheckMate 017/057	Nivolumab vs docetaxel	OS	HR = 0.68, 95%CI: 0.50-0.91	HR = 0.70	Nivolumab maintained an OS benefit, similar to the overall population
NSCLC[83]	KEYNOTE-189	Pembro + chemo vs chemo	OS	HR = 0.62, 95%CI: 0.44-0.87)	HR = 0.56	OS benefit was present but less pronounced than in the overall population
NSCLC[84-87]	Meta-analyses of KEYNOTE-001, KEYNOTE-010, and KEYNOTE-024	ICIs vs control (pooled analysis)	OS	Pooled OS: HR = 0.78, 95%CI: 0.68-0.90	N/A	Survival benefit is present but attenuated relative to patients without liver involvement (ratio of OS-HRs = 1.10)
NSCLC[88]	Real-world cohorts	ICI-treated patients (with vs without liver mets)	OS	N/A	N/A	Approximately 21% higher risk of death (OS: HR = 1.21, 95%CI: 1.17-1.27) with liver metastases
NSCLC[89-91]	IMpower150 (final analysis)	ABCP (atezolizumab + bevacizumab + chemo) vs chemo	OS	HR = 0.68, 95%CI: 0.45-1.02	N/A	Suggested clinically meaningful benefit by adding anti-VEGF (bevacizumab) to the regimen in this subgroup
NSCLC[92,93]	CheckMate 9 LA	Nivo + ipi + chemo vs chemo	OS (5-year rate)	Numerically lower survival than those without hepatic mets; 18% OS rate (vs 11% with chemo alone)	N/A	Durable OS benefit across metastatic subgroups, including those with liver involvement
Melanoma[94]	-	Anti-PD-1 therapy (pooled analyses)	ORR	Markedly reduced	N/A	Liver metastases significantly dampen responses, associated with reduced CD8+ T-cell infiltration
CRC[99]	KEYNOTE-177 (MSI-H/dMMR subset)	Pembrolizumab vs chemotherapy	PFS	Improved PFS (specific HR not provided)	N/A	Pembrolizumab significantly improved PFS, including those with liver metastases
CRC[106]	Real-world, MSI-H/dMMR)	ICI-treated patients (with vs without liver mets)	ORR, PFS	ORR = 58%; PFS: HR = 3.18, 95%CI: 1.52-6.67	ORR 66%	Liver involvement impairs outcomes (lower ORR, higher HR for progression)
CRC[108]	REGONIVO (regorafenib + nivolumab, early-phase)	ICI + VEGF inhibitor	ORR	7%-19% (North American cohorts)	Up to 33% (Japanese cohorts)	Limited generalizability; ORR significantly lower, especially in patients with liver metastases
PDAC[123,125]	KEYNOTE-158 (MSI-H/dMMR subset)	Pembrolizumab	OS, ORR	ORR = 18% (4 of 22 patients); median OS = 4.0 months, 95%CI: 2.1-8.7	N/A	Limited data; liver metastases exacerbate resistance due to fibrosis-driven immune exclusion
Gastric/GEJ cancer[129]	KEYNOTE 859	Chemo-immunotherapy combination	OS	HR = 0.83, 95%CI: 0.70-0.90	HR = 0.73, 95%CI: 0.63-0.84	Survival benefits regardless of liver metastasis status; difference in benefit was not statistically significant
Gastric/GEJ cancer[131]	Retrospective cohort	ICI-treated patients (with vs without liver mets)	OS	10.53 months	13.43 months	No significant difference in OS. Other factors (peritoneal mets, burden) were more strongly associated with reduced PFS
Gastric/GEJ[126]	Mechanistic profiling	-	Immune composition (CD4+, CD8+, monocytic MDSC)	-	Stomach/GEJ show increase proliferating CD4+/CD8+ and decrease monocytic MDSC vs EAC	Proinflammatory TME may blunt LM’s negative effect
Gastric/GEJ[127]	JAVELIN gastric 100 - phase 3 (maintenance)	Avelumab maintenance vs maintenance chemotherapy	OS, PFS	Not reported specifically by LM status	No improvement in OS or PFS with avelumab maintenance	Maintenance ICI alone did not improve outcomes
Gastric/GEJ[128-130]	Meta-analysis	Chemoimmunotherapy vs chemotherapy	OS, PFS	Benefit observed irrespective of LM status across included trials	ChemoIO improved OS and PFS (KEYNOTE859, CheckMate 649)	Supports chemoIO regardless of LM status
Gastric/GEJ[130]	CheckMate 649 - phase 3	Nivolumab + chemo vs chemo	OS, PFS	No dedicated LM subgroup analysis reported	Significant OS/PFS benefit overall (approximately 96% metastatic; approximately 40% LM)	ChemoIO improves outcomes; LMspecific effect not isolated
Gastric/GEJ[129]	KEYNOTE859 - phase 3	Pembrolizumab + chemo vs chemo	OS	HR = 0.83, 95%CI: 0.70-0.90 - benefit regardless of LM	NoLM HR = 0.73, 95%CI: 0.63-0.84	Difference by LM not statistically significant
Gastric/GEJ[131]	Retrospective cohort	Immunotherapy (with LM vs without LM)	OS (factors for PFS)	OS = 10.53 months (LM) - no significant difference vs noLM	OS = 13.43 months (noLM); P = 0.584	Reduced PFS associated with MMR mutations, > 3 metastatic sites, peritoneal metastases

ICI: Immune checkpoint inhibitor; N/A: Not applicable; VEGF: Vascular endothelial growth factor; PD-1: Programmed cell death 1; MSI-H: Microsatellite instability-high; dMMR: Mismatch repair-deficient; MDSC: Myeloid-derived suppressor cell; GEJ: Gastroesophageal junction; EAC: Esophageal adenocarcinoma; NSCLC: Non-small cell lung cancer; CRC: Colorectal cancer; PDAC: Pancreatic ductal adenocarcinoma; OS: Overall survival; PFS: Progression free survival; ORR: Objective response rate; TME: Tumor microenvironment; LM: Liver metastasis.

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.

Table 4 Summary of clinical evidence for ablative therapies in liver metastases across tumor types

Technique	Typical local control rate	Any OS benefit in RCTs	Comments
RFA[169]	80%-95% (CRLM)	Yes (CLOCC: 8-year OS 35.9% vs 8.9%, HR = 0.58, P = 0.01)	Effective for small, oligometastatic CRLM; potentially curative; added to systemic therapy in unresectable CRLM
MWA[174,175]	≥ 85% (various primaries)	Not reported	May outperform RFA for perivascular tumors due to reduced heat-sink effects
Cryoablation[169]	≥ 85% (various primaries)	Not reported	High local control for breast, lung, neuroendocrine metastases; symptom palliation
SBRT[169]	83%-94% (small lesions < 3 cm)	Not reported	Minimal grade ≥ 3 toxicity (< 10%)
Ablation (general)[171,172]	80%-95% (CRLM)	Yes (collision: HR = 1.05, P = 0.83, non-inferior to surgery)	Non-inferior to surgery for OS and local control in CRLM; promising with ICI
Ablation + ICI[177,178]	Not specified	Yes (IMbrave050: Improved RFS/OS vs ICI alone)	Improved RFS/OS in HCC; unconfirmed long-term OS benefit; EORTC-1560 ILOC showed no response in untreated metastases

ICI: Immune checkpoint inhibitor; OS: Overall survival; RFS: Recurrence-free survival; HCC: Hepatocellular carcinoma; RFA: Radiofrequency ablation; CRLM: Colorectal liver metastases; RCT: Randomised controlled trial; MWA: Microwave ablation; SBRT: Stereotactic body radiotherapy.