Microbiome dysbiosis and immune checkpoint inhibitors: Dual targets in Hepatocellular carcinoma management

Table 1 Immune checkpoint inhibitors efficacy in hepatocellular carcinoma

Study name	Regimen	Line of therapy	No. of patients	ORR (%)	mPFS (months)	mOS (months)	Findings
ICI single therapy
CheckMate 459[7,36]	Nivolumab vs Sorafenib	1st line	743	15	3.7 vs 3.8	16.4 vs 14.7	HR death 0.85 (95%CI: 0.72-1.00; P = 0.0522)
Keynote-224[9]	Pembrolizumab	2nd line	104	17	4.9	13.2	Durable anti-tumour activity and improvement in BOR. CR increased vs the primary analysis (3.8% vs 1.0%)
Keynote-240[8]	Pembrolizumab vs Placebo	2nd line	413	18 vs 4	3.0 vs 2.8	13.9 vs 10.6	Did not met the threshold HR of 0.781 (95%CI: 0.611 to 0.998; P = 0.0238) and 0.775 (95%CI: 0.609-0.987; P = 0.0186) for OS and PFS
Keynote-394[37]	Pembrolizumab vs Placebo	2nd line (Asian)	453	13.9 vs 1.3	2.6 vs 2.3	14.6 vs 13.0	Significance OS/PFS benefit (HR = 0.79; 95%CI: 0.63-0.99; P = 0.018)
HIMALAYA[38]	STRIDE (Durva + Tremeli) vs Sorafenib	1st line	1171	20.1	3.78 vs 4.07	16.4 vs 13.8	Significance OS (HR = 0.78; 96%CI: 0.65–0.92; P = 0.0035)
RATIONALE-301[39]	Tislelizumab vs Sorafenib	1st line	674	14.3 vs 5.4	2.3 vs 3.3	15.9 vs 14.1	OS non-inferior (HR = 0.85; 95%CI: 0.712-1.019)
Sangro et al[40] 2013	Tremelimumab	2nd line	21	17.6	NA	8.2	Median TTP 6.48 months (95%CI: 3.95–9.14)
ICI combination therapies
CheckMate 040[47]	Nivolumab + Ipilimumab	2nd line	148	32-31	2.96-4.0	22.8-12.5	Arm A, the 12-mOS rate was 61% (95%CI: 0.46-0.73)
CheckMate 9DW[46]	Nivolumab + Ipilimumab vs Sorafenib/Lenvatinib	1st line	1084	36 vs 13	9.1 vs 9.2	23.7 vs 20.6	Significantly improve OS (HR = 0.79, 95%CI: 0.65-0.96; P = 0.018)
IMbrave150[43]	Atezolizumab + Bevacizumab vs Sorafenib	1st line	336 vs 165	27.3 vs 11.9	6.8 vs 4.3	19.1 vs 13.4	HR death 0.58 (95%CI 0.42–0.79; P < 0.001)
AMETHISTA[44]	Atezolizumab + Bevacizumab (Single arm)	1st line	152	26.9	8.51	18.23	TEAEs in 28.9%
COSMIC-312[45]	Atezolizumab Cabozantinib vs sorafenib	1st line	837	NA	6.8 vs 4.2	15.4 vs 15.5	HR death 0.63 (95%CI: 0.44-0.91, P = 0.0012)

HR: Hazard risk; BOR: Best overall response; CR: Complete response; OS: Overall survival; PFS: Progression-free survival; TTP: Time to progression; TEAE: Treatment-emergent adverse events.

Table 2 Gut microbiome modulation to enhanced immune checkpoint inhibitors outcome

Ref.	Country	Samples (n)	Microbiota enrichment or microbiota modulation	ICIs	Outcomes
Zheng et al[138] (2020)	China	HCC with BCLC C (n = 8)	Firmicutes, Bacteroidetes, Proteobacteria dominated both in responder and non-responder	Camrelizumab (Anti-PD-1)	Several beneficial lactic acid bacteria, including four Lactobacillus species (L. oris, L. vaginalis, L. mucosae, and L. gasseri), Streptococcus thermophilus, and Bifidobacterium dentium, were significantly enriched, contributing to the support of host metabolism and immune function. Additionally, commensal bacteria enriched in responders—particularly members of the Ruminococcaceae family and Akkermansia muciniphila—promoted host health by preserving intestinal barrier integrity and mitigating systemic immunosuppression
Mao et al[113] (2021)	China	Unresectable HCC (n = 35) or advanced biliary tract cancer (n = 30)	Bacteroidetes, Proteobacteria, and Firmicutes dominated in both the clinical benefit response (CBR) group and the non-clinical benefit response (NCB) group	Anti-PD-1 (patients that progressed from gemcitabine plus cisplatin and the first-line chemotherapy)	The CBR group had more Bacteroidetes (P = 0.028), while Proteobacteria trended higher in the NCB group (P = 0.067). In HCC patients, Veillonellaceae was enriched in the NCB group and linked to poorer outcomes. In contrast, Erysipelotrichaceae bacterium-GAM147 and Ruminococcus callidus were associated with longer progression-free survival. These findings suggest that gut microbiota composition influences ICI response and survival
Shen et al[114] (2021)	Taiwan	Advanced HCC (n = 36)	Bifidobacterium, coprococcus, acidaminococcus	Anti-PD-1/anti-PD-L1 monotherapy or in combination with an immunomodulatory agent	Responders showed higher levels of Succinivibrio and Tyzzerella subgroup 4, while nonresponders had more Akkermansia. However, in patients with disease control, significant enrichment was observed in Bifidobacterium, Alloprevotella, Blautia, Megasphaera, Succinatimonas, Lachnospira, Acidaminococcus, Tyzzerella subgroup 4, and Coprococcus subgroup 3. Notably, by week 8 of ICI therapy, the increased abundance of Bifidobacterium, Acidaminococcus, and Coprococcus was no longer present
Lee et al[140] (2022)	Taipei	Unresectable HCC	Firmicutes and bacteroides	Nivolumab and pembrolizumab	Lachnospiraceae and Veillonellaceae were enriched in responders, while Prevotellaceae and Enterobacteriaceae increased in progressive disease with reduced Lachnospiraceae and Veillonellaceae. Secondary bile acids (e.g., UDCA, MDCA, tauro-UDCA, UCA) were higher in responders and correlated positively with Lachnoclostridium and Ruminococcus gnavus, but negatively with Prevotella 9. High Lachnoclostridium and low Prevotella 9 were linked to improved overall survival (median OS: 22.8 months)
Ahmed et al[55] (2018)	New York	Advance cancer (n = 60), HCC (n = 5)	Systemic antibiotic. Broad spectrum antibiotic (including cephalosporin). Narrow spectrum antibiotic (including vancomycin)	Anti-PD-1 or anti-PDL-1	Broad-spectrum antibiotics were linked to poorer treatment responses compared to narrow-spectrum antibiotics. Using antibiotics shortly before or after starting ICI therapy was associated with shorter progression-free survival. Overall, patients who received antibiotics had worse overall survival than those who did not

BCLC: Barcelona-clinic liver cancer; HCC: Hepatocellular carcinoma; PD-1: Programmed cell death 1; PDL-1: Programmed death-ligand 1; ICI: Immune checkpoint inhibitor; CBR: Clinical benefit response; NCB: Non-clinical benefit.