Immune escape mechanisms revealed by multifunctional nanoprobes targeting PD‐L1 in hepatic cancer progression

Abstract Hepatocellular carcinoma (HCC) often arises from liver cirrhosis, yet real‐time, noninvasive monitoring of immune escape during this transition remains limited. We developed a multifunctional biomimetic nanoprobe (ICGB@Apt) by conjugating a programmed death‐ligand 1 (PD‐L1)–specific DNA aptamer (selected via Cell–SELEX) onto an indocyanine green/BMS‐684 polymer, enabling in vivo imaging and immune modulation. In CCl 4 ‐induced mouse models progressing from cirrhosis to HCC and in complementary in vitro 3D co‐culture systems, ICGB@Apt preferentially accumulated in tumor tissue, dynamically visualized PD‐L1, and mitigated disease progression. The probe enhanced CD8 + T‐cell activity (IFN‐γ and granzyme B), reduced fibrosis and tumor burden, and outperformed non‐aptamer controls (Apt+ICG or ICGB alone). Knockdown experiments and RNA‐seq highlighted the centrality of the programmed death‐1 (PD‐1)/PD‐L1 axis; immune deconvolution implicated CD8 + T cells, follicular helper T cells, and M0 macrophages in the cirrhosis‐to‐cancer shift. The nanoprobes showed favorable biocompatibility and enabled longitudinal tracking of primary and metastatic lesions. Together, these findings establish ICGB@Apt as a PD‐L1–targeted platform that simultaneously monitors and counteracts immune escape, offering translational potential for early detection and immunotherapy guidance in HCC.