Hepatocellular carcinoma (HCC) is commonly diagnosed at intermediate or advanced stages. While transcatheter arterial embolization (TAE) is the accepted locoregional therapy, embolization inevitably induces severe intratumoral hypoxia, leading to excessive lactate accumulation, metabolic reprogramming and the formation of an immunosuppressive tumor microenvironment (TME), factors that collectively limit durable therapeutic efficacy and promote tumor recurrence. Although immunotherapy has shown promise in HCC, the efficacy of combining TAE with immune-based strategies remains suboptimal, largely due to metabolic constraints and T cell dysfunction within the post-embolization TME. Interleukin-2 (IL-2) therapy can stimulate effector T cells but suffers from the drawbacks of systemic toxicity, a short half-life and TME-induced dysfunction. Recent evidence indicates that lactate-rich, acidic TMEs impair IL-2 stability and signaling, suppress CD8⁺ T cell function, and promote Treg cell activity, thereby further compromising IL-2-based immunotherapy following TAE. Here, we developed a nano-immunotherapy platform (Syr/IL-2@MPDA) using mesoporous polydopamine (MPDA) nanoparticles co-loaded with His-tagged IL-2 and the monocarboxylate transporter inhibitor Syrosingopine (Syr). Syr-mediated lactate regulation alleviates TME acidity and restores IL-2 activity, while MPDA enables mild photothermal therapy (mPTT) to transform immunologically "cold" tumors into "hot" phenotypes, thereby enhancing the immune response. This integrated strategy significantly enhanced antitumor immunity, achieving a tumor growth inhibition rate of 70.87% in a murine subcutaneous tumor model. In an orthotopic N1S1 HCC rat model, the treatment demonstrated strong therapeutic efficacy in combination with αPD-L1 and TAE, overcoming the hazards of TAE-induced lactate accumulation and immune suppression. Overall, this study demonstrates a safe and effective strategy that enhances IL-2 immunotherapy through mPTT and metabolic modulation, offering a promising combination treatment for advanced HCC.
Keywords: Cancer immunotherapy; Interleukin-2; T cell activation.
© 2026 Shenyang Pharmaceutical University. Published by Elsevier B.V.