Background: The macrotrabecular-massive (MTM) is a special subtype of hepatocellular carcinoma (HCC), which has commonly a dismal prognosis. This study aimed to develop a multitask deep learning radiomics (MDLR) model for predicting MTM and HCC patients’ prognosis after hepatic arterial infusion chemotherapy (HAIC). Methods: From June 2018 to March 2020, 158 eligible patients with HCC who underwent surgery were retrospectively enrolled in MTM related cohorts, and 752 HCC patients who underwent HAIC were included in HAIC related cohorts during the same period. DLR features were extracted from dual-phase (arterial phase and venous phase) contrast-enhanced computed tomography (CECT) of the entire liver region. Then, an MDLR model was used for the simultaneous prediction of the MTM subtype and patient prognosis after HAIC. The MDLR model for prognostic risk stratification incorporated DLR signatures, clinical variables and MTM subtype. Findings: The predictive performance of the DLR model for the MTM subtype was 0.968 in the training cohort [TC], 0.912 in the internal test cohort [ITC] and 0.773 in the external test cohort [ETC], respectively. Multivariable analysis identified portal vein tumor thrombus (PVTT) (p = 0.012), HAIC response (p < 0.001), HAIC sessions (p < 0.001) and MTM subtype (p < 0.001) as indicators of poor prognosis. After incorporating DLR signatures, the MDLR model yielded the best performance among all models (AUC, 0.855 in the TC, 0.805 in the ITC and 0.792 in the ETC). With these variables, the MDLR model provided two risk strata for overall survival (OS) in the TC: low risk (5-year OS, 44.9%) and high risk (5-year OS, 4.9%). Interpretation: A tool based on MDLR was developed to consider that the MTM is an important prognosis factor for HCC patients. MDLR showed outstanding performance for the prognostic risk stratification of HCC patients who underwent HAIC and may help physicians with therapeutic decision making and surveillance strategy selection in clinical practice.

Background: Portal vein tumor thrombosis (PVTT) signifies late-stage hepatocellular carcinoma (HCC) with high-risk progression and poor prognosis. As a standard treatment, sorafenib monotherapy has limited the efficacy in managing HCC with PVTT. Currently, both hepatic arterial infusion chemotherapy (HAIC) and the combination of camrelizumab and rivoceranib have shown favorable survival benefits for advanced HCC, surpassing the standard sorafenib treatment. In this study, we investigate the safety and efficacy of HAIC combined with camrelizumab and rivoceranib in treating HCC patients with PVTT. Methods: From January 2020 to December 2021, HCC patients with PVTT, who received either a triple regime of HAIC combined with camrelizumab and rivoceranib or a dual regime of camrelizumab and rivoceranib as their first-line treatment, were reviewed for eligibility at four hospital centers in China. To balance any intergroup differences, propensity score matching (PSM) was applied. The aim of this study is to compare the efficacy of the dual and triple combination treatment regimens based on survival prognosis and tumor response and evaluate the safety based on the occurrence of adverse reactions. Result: In this study, a total of 411 patients who received either the triple treatment regime (HAIC combined with camrelizumab plus rivoceranib, referred to as the HAICCR group, n = 292) or the dual treatment regime (camrelizumab combined with rivoceranib, referred to as the CR group, n = 119) between January 2020 and December 2021 were included. The results showed that the HAICCR group exhibited significantly better overall survival (mOS: 19.60 months vs. 11.50 months, p < 0.0001) and progression-free survival (mPFS: 10.0 months vs. 5.6 months, p < 0.0001) compared to the CR group in the overall cohort. Moreover, the HAICCR group also had a significantly higher ORR (objective response rate, 55.5% vs. 42.0%, p = 0.013) and DCR (disease control rate, 89.0% vs. 79.0%) compared to the CR group. After PSM, a final matched cohort of 83 pairs was obtained, and the survival benefits were consistent in this cohort as well (mOS: 18.70 months vs. 11.0 months, p < 0.0001; mPFS: 10.0 months vs. 5.6 months, p < 0.0001). However, there was no significant difference in the ORR between the triple and dual combination regimes. Univariate and multivariate analysis showed that CTP (Child–Turcotte–Pugh) stage, ALBI (albumin–bilirubin index) grade, tumor number, and treatment regime were significant risk factors affecting overall survival, while AFP (α-fetoprotein) level, tumor number, metastasis, and treatment regime were significant risk factors affecting progression-free survival. As for safety, hypertension and hand–foot syndrome were the two most common adverse reactions in both groups, with no significant difference in the occurrence of adverse reactions between the two groups (p < 0.05). Conclusion: In the context of advanced HCC patients with PVTT, the combination regime of HAIC and camrelizumab plus rivoceranib demonstrates more excellent capacity for prolonging survival and offers a well-tolerated safety compared to the CR dual therapy approach. This triple regime represents a therapeutic modality of broad prospects and vast potential for HCC patients with PVTT.

Background: Although peripheral blood lymphocyte subsets, particularly PD-1+ T cells, are promising prognostic indicators for patients with cancer. However, their clinical significance remains unclear.Methods: We prospectively enrolled 157 patients with hepatocellular carcinoma (HCC) treated with transcatheter arterial chemoembolization combined with or without PD-1 inhibitors. Twenty peripheral lymphocyte subsets and cytokines were analyzed. We analyzed the differences in PD-1+ T cells between patients treated with and without PD-1 inhibitors and their associations with tumor response, survival prognosis, and clinical features.Results: We found that the baseline CD8+PD-1+ and CD4+PD-1+ T-cell frequencies in patients who had received PD-1 inhibitors were lower than those in patients who had not received PD-1 inhibitors (p < 0.001). In the former patients, there were no differences in PD-1+ T-cell frequencies between the responder and non-responder subgroups (p > 0.05), whereas in the latter patients, the levels of CD8+PD-1+ T cells, CD4+PD-1+ T cells, and CD8+PD-1+/CD4+PD-1+ ratio did not predict tumor response, progression-free survival (PFS), or overall survival (OS) (p>0.05). Furthermore, in multivariate analysis of patients treated with or without PD-1 inhibitors revealed that the levels of CD8+CD38+ T cells (OR = 2.806, p = 0.006) were associated with tumor response, whereas those of CD8+CD28+ T cells (p = 0.038, p = 0.001) and natural killer (NK) cells (p = 0.001, p = 0.027) were associated with PFS and OS. Although, these independent prognostic factors were associated with progressive tumor characteristics (p 0.05).Conclusion: Circulating CD8+CD38+ T cells, CD8+CD28+ T cells, and NK cells were identified as potential prognostic factors for tumor response and survival in patients with HCC. Contrastingly, although PD-1 inhibitors can effectively block the T cell PD-1 receptor, the baseline PD-1+ T-cell frequencies and changes in the frequency of these cells have limited prognostic value.

Background: Transarterial chemoembolization (TACE) treats inoperable liver cancer by inducing tumor ischemia, but subsequent hypoxia can promote an immunosuppressive microenvironment. This study explores how TACE-related hypoxia influences immune cells through lactate metabolism and lactylation. Methods: Single-cell RNA sequencing of TACE-treated and newly diagnosed liver cancer samples was performed. Scores were assigned to lactate-related gene sets, and differentially expressed genes were identified. Bioinformatics analysis integrated scRNA-seq, TCGA, and GEO data. Machine learning derived a consensus gene signature, and a prognostic nomogram was constructed. The study evaluated immune infiltration and drug sensitivity. Key findings were validated via spatial transcriptomics, in vitro experiments, and immunofluorescence. Results: We identified seven distinct single-cell types, noting an increase in macrophage infiltration and a decrease in CD8+ T cells within the TACE group. A six-gene consensus signature related to lactate—comprising SPP1, DNASE1L3, HRG, TPX2, LAPTM4B, and G6PD—was identified and found to be significantly associated with poor prognosis. This consensus gene score and T, N staging constructed a prognostic nomogram validated by calibration curves and decision curves. We also found that SPP1+ macrophages were elevated in the TACE treatment group, with increased lactate-related gene set scores, and were associated with hypoxia, glycolysis, and inflammatory pathways. Cell communication analysis suggested a potential regulatory link between SPP1+ macrophages and CD8+ T cells, highlighting the potential involvement of the SPP1-CD44 axis. Cell experiments showed that hypoxic, lactate-rich environments lead to macrophage lactylation, increasing SPP1+ macrophages and decreasing CD8+ IFN-γ+ T cells. Spatial transcriptomics and immunofluorescence staining revealed co-localization of SPP1+ macrophages with CD8+ T cells. Conclusion: We established a lactate-associated six-gene signature and prognostic nomogram. The immunosuppressive microenvironment following TACE in liver cancer is highly correlated with the activation of lactate-related genes and an increase in SPP1+ macrophages. These macrophages are closely associated with CD8+ T cells dysfunction, with the SPP1-CD44 pathway serving as a candidate narrative for this intercellular crosstalk. These findings suggest that targeting lactate-induced lactylation or the potential SPP1-CD44 interaction may offer promising therapeutic opportunities to counteract immune evasion after TACE therapy.