Heterogeneity of hepatocellular carcinoma that responds differently to combination therapy with TACE and Sorafenib as determined by digital spatial gene expression profiling.

Background: The combination of Sorafenib and transcatheter arterial chemoembolization (TACE) exhibits limited efficacy in the treatment of certain advanced hepatocellular carcinomas (HCC), and the molecular mechanisms underlying resistance to this combination remain unclear.

Objective: This study aims to underscore the distinctive contribution of GeoMx DSP technology in elucidating the molecular intricacies of HCC resistance to the Sorafenib and TACE combination.

Methods: Patients with advanced HCC during the waiting period before liver transplantation were classified into sensitive and resistant groups based on their response to Sorafenib and TACE combination therapy. Employing GeoMx DSP technology for comprehensive gene expression profiling, we identified pivotal molecular targets linked to resistance against combination therapy.

Results: The investigation scrutinized intra-tumoral and inter-individual variances, unveiling a spectrum of crucial molecular targets, such as PLG, PLVAP, immunoglobulin genes, ORM1, and NR4A1, among others. Additionally, we explored signaling pathways associated with treatment responsiveness, including the PPAR signaling pathway. Notably, we emphasized the significance of the immune microenvironment characterized by heightened SPP1 expression in HCC resistance to combination therapy. In the resistant group, SPP1⁺ tumor-associated macrophage (TAM) infiltration was notably pronounced (p = 0.037), while T-cell depletion showed a mitigated presence (p = 0.013).

Conclusion: The study reveals intra- and inter-individual heterogeneity in HCC that is differentially responsive to the combination of Sorafenib and TACE, highlighting multiple key molecular targets associated with treatment resistance. The immune microenvironment is important, and in particular, SPP1⁺ TAM infiltration may play a key role. Meanwhile, the introduction of immunotherapy in patients resistant to combination therapy may lead to positive results.