Enhanced formation of tertiary lymphoid structures shapes the anti-tumor microenvironment in hepatocellular carcinoma after FOLFOX-HAIC therapy.

Tertiary lymphoid structures (TLSs) emerge as crucial determinants of anti-tumor immune responses and clinical outcomes. However, their clinical significance and formation mechanisms in hepatocellular carcinoma (HCC) remain unclear. Here, we demonstrate that hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and fluorouracil (FOLFOX) significantly enhances TLS formation in HCC tissues, correlating with improved therapeutic efficacy and prolonged progression-free survival in patients with HCC. Mechanistically, HAIC induces lymphotoxin β (LTβ)-expressing central memory T cell (T_CM)-like CD4⁺ T cells, which activate MMP2⁺ fibroblasts and FOLR2⁺CCL4⁺ macrophages via the LTβ-LTβR axis to drive TLS development. Furthermore, the CXCL12-CXCR4 axis acts as a critical mediator in recruiting these cells to HAIC-treated tumors, thereby facilitating TLS formation and enhancing anti-tumor immunity. These findings highlight the pivotal role of TLSs in HAIC-induced anti-tumor immunity and their significance as robust prognostic biomarkers, offering potential therapeutic targets to optimize clinical outcomes for patients with HCC.