Background/Objectives: The aim of this study was to investigate the prognostic value of established response assessment tools for hepatocellular carcinoma (HCC) treated with high-dose-rate interstitial brachytherapy (iBT) alone or with transarterial chemoembolization (cTACE). Methods: (Non-)responders were categorized using size-based RECIST 1.1 and WHO criteria, enhancement-based mRECIST and EASL criteria, and the LI-RADS Treatment Response Algorithm (LR-TRA). The outcomes were the overall survival (OS), progression-free survival (PFS), and time to progression (TTP). The statistics used included Fisher’s exact test, a t-test, the Mann–Whitney-U test, and a Kaplan–Meier analysis. The median OS, PFS, and TTP were higher in patients following iBT (26.3, 9.1, and 13.0 months) than following cTACE/iBT (23.3, 7.6, and 9.2 months). Results: The enhancement-based criteria identified more responders and predicted PFS and TTP better compared to the size-based criteria. At two months, the cTACE/iBT responders showed improved PFS (mRECIST and EASL: 11.3 vs. 2.3 and 11.0 vs. 2.3, p < 0.01) and TTP (mRECIST and EASL: 11.9 vs. 2.4 months, p < 0.01) by the enhancement-based criteria. An EASL assessment at five months predicted improved survival following both cTACE/iBT (PFS: 11.9 vs. 5.1 months, p = 0.03; TTP: 12.4 vs. 5.0, p < 0.01) and iBT (11.1 vs. 5.1 months, p = 0.04; 13.0 vs. 5.3, p < 0.01). The LR-TRA showed OS benefits at five months for cTACE/iBT responders. Size-based criteria were not prognostic. Conclusions: Extending follow-up post-iBT or post-iBT/cTACE may improve responder stratification and prognostication.

M2-like macrophages promote tumor growth and cancer immune evasion. This study used an in vitro model to investigate how hypoxia and tumor metabolism affect macrophage polarization. Liver cancer cells (HepG2 and VX2) and macrophages (THP1) were cultured under hypoxic (0.1% O₂) and normoxic (21% O₂) conditions with varying glucose levels (2 g/L or 4.5 g/L). Viability assays and extracellular pH (pHe) measurements were conducted over 96 hours. Macrophages were exposed to the tumor-conditioned medium (TCM) from the cancer cells, and polarization was assessed using arginase and nitrite assays. GC-MS-based metabolic profiling quantified TCM meta-bolites and correlated them with M2 polarization. The results showed that pHe in TCMs decreased more under hypoxia than normoxia (p < 0.0001), independent of glucose levels. The arginase assay showed hypoxia significantly induced the M2 polarization of macrophages (control group: p = 0.0120,^0.1%VX2-TCM group: p = 0.0149, ^0.1%HepG2-TCM group: p < 0.0001, ^0.1%VX2-TCM_HG group: p = 0.0001, and ^0.1%HepG2-TCM_HG group: p < 0.0001). TCMs also induced M2 polarization under normoxic conditions, but the strongest M2 polarization occurred when both tumor cells and macrophages were incubated under hypoxia with high glucose levels. Metabolomics revealed that several metabolites, particularly lactate, were correlated with hypoxia and M2 polarization. Under normoxia, elevated 2-amino-butanoic acid (2A-BA) strongly correlated with M2 polarization. These findings suggest that targeting tumor hypoxia could mitigate immune evasion in liver tumors. Lactate drives acidity in hypoxic tumors, while 2A-BA could be a therapeutic target for overcoming immunosuppression in normoxic conditions.