Transforming Cold Tumors into Hot Ones with a Metal–Organic Framework-Based Biomimetic Nanosystem for Enhanced Immunotherapy

Abstract

Immunotherapy has revolutionized the landscape in clinical tumor therapy, although the response rates in "cold" tumors are relatively low owing to the complex tumor microenvironment (TME). Cyclic guanosine monophosphateadenosine monophosphate synthase/stimulator of interferon genes (cGAS/STING) pathway-inducing agents can reprogram the TME; however, their applications remain underutilized. Herein, we engineered a facile manganese-based metal−organic framework (Mn-MOF) encapsulating polyphyllin I (PPI) and coated it with red blood cell (RBC) membranes (RBC@Mn-MOF/PPI) that enhanced the cGAS/ STING-mediated antitumor immunity. RBC@Mn-MOF/PPI was engineered by camouflaging it with a biomimetic RBC membrane for prolonged blood circulation and immune escape, which was also extended with TME-sensitive properties for triggering the release of PPI and Mn 2+ to remodel the suppressive TME and augment antitumor immune responses. Furthermore, RBC@Mn-MOF/PPI helped transform cold tumors into "hot" ones by activating immune cells, as evidenced via dendritic cell maturation, cytotoxic T lymphocyte infiltration, and natural killer cell recruitment, thereby targeting primary and abscopal tumors and lung metastatic nodules. Therefore, our engineered nanosystem represents a novel strategy to transform immunologically "cold" tumors into "hot" ones by activating the cGAS/STING pathway, thereby addressing the major challenges associated with immunotherapy.

Engineering Au44 Nanoclusters for NIR-II Luminescence Imaging-Guided Photoactivatable Cancer Immunotherapy

“…As reported, the PTT of in situ tumors can transform them from "cold" tumors into "hot" ones, thus promoting various immune cells to infiltrate the tumor site and trigger tumor-specific immune response. 54,55 Moreover, the PDT effect of the probe also synergistically contributes to tumor therapy. Besides, the photoactivatable release of NLG919 from Au 44 MBA 26 -NLG could reverse the immunosuppressive microenvironment, enhance tumor suppression, and also generate systemic immune memory to prevent tumor recurrence.…”

Biomimetic Nano-Drug Delivery System: An Emerging Platform for Promoting Tumor Treatment

“…Research demonstrates that particles closely emulating healthy RBCM exhibit superior anti-tumor effects, offering insights for tailored carriers and personalized treatment ( Figure 3B ). To overcome traditional immunotherapy limitations, Xu et al 86 developed a BNDDS by encapsulating Mn-based MOFs loaded with polyphyllin I within RBCM. BNDDS demonstrated superior anti-tumor effects compared to traditional immunotherapy by activating the cGAS/STING pathway ( Figure 3C ).…”

Metal–Organic Framework Nanocomposites in Conquering Hypoxia for Tumor Therapy

“…[143,144] However, the tumor hypoxic environment seriously affects antitumor effects of immune system, suppresses various immune cell functions including macrophages, DCs, monocytes, T cells, and causes severe immune resistance. [37] Owing to high loading capacity, suitable size, diverse compositions, adjustable pore sizes, and EPR of MOFs, they have been widely used as nanocarriers in immunotherapy to load therapeutic agents such as antigens, adjuvants, and immunomodulators and applied for overcoming tumor hypoxia and enhancing therapeutic effects [145][146][147][148] (Figure 23).…”