Hepatocellular carcinoma (HCC) has been known as the second common leading cancer worldwide, as it responds poorly to both chemotherapy and medication. Triptolide (TP), a diterpenoid triepoxide, is a promising treatment agent for its effective anticancer effect on multiple cancers including HCC. However, its clinical application has been limited owing to its severe systemic toxicities, low solubility, and fast elimination in the body. Therefore, to overcome the above obstacles, photo-activatable liposomes (LP) integrated with both photosensitizer Ce6 and chemotherapeutic drug TP (TP/Ce6-LP) was designed in the pursuit of controlled drug release and synergetic photodynamic therapy in HCC therapy. The TP encapsulated in liposomes accumulated to the tumor site due to the enhanced permeability and retention (EPR) effect. Under laser irradiation, the photosensitizer Ce6 generated reactive oxygen species (ROS) and further oxidized the unsaturated phospholipids. In this way, the liposomes were destroyed to release TP. TP/Ce6-LP with NIR laser irradiation (TP/Ce6-LP+L) showed the best anti-tumor effect both in vitro and in vivo on a patient derived tumor xenograft of HCC (PDXHCC). TP/Ce6-LP significantly reduced the side effects of TP. Furthermore, TP/Ce6-LP+L induced apoptosis through a caspase-3/PARP signaling pathway. Overall, TP/Ce6-LP+L is a novel potential treatment option in halting HCC progression with attenuated toxicity.

Hypoxia leads to up‐regulation of PD‐L1 and decreases T lymphocyte infiltration, thus boosting immunotherapeutic resistance of tumors. Moreover, tumor‐infiltrating myeloid cells such as myeloid‐derived suppressor cells (MDSCs) correlate with potent immune suppressive activity and resistance to the immune checkpoint blocking (ICB) in tumor sites. Here, a multifunctional nanoregulator incorporating MnO₂ particles and small molecular IPI549 is developed, which can reshape the tumor immune microenvironment (TIME) to unleash the immune system. The intravenously administered nanoregulator effectively accumulates in tumor sites to alleviate hypoxia via oxygen‐generating reduction of MnO₂ and to inhibit PI3Kγ on MDSCs via IPI549 release in the tumor microenvironment (TME), which results in concurrent downregulation of PD‐L1 expression, polarization of tumor associated macrophages (TAMs) toward pro‐inflammatory M1‐like phenotype (tumor‐suppressive), enhanced infiltration of CD4⁺ helper T lymphocytes (Th cells), and cytotoxic CD8⁺ T lymphocytes (Tc cells), and suppressed infiltration of regulatory T lymphocytes (T_reg cells) for effective tumor immunotherapy. Furthermore, the local generation of Mn²⁺ in TME allows tumor‐specific magnetic resonance imaging (MRI). More excitingly, the nanoregulator‐reshaped TIME is effectively reserved due to the synergistic effect of hypoxia alleviation and MDSC PI3Kγ inhibition, leading to remarkable post‐medication inhibition of tumor re‐growth and metastasis in an animal study.