Large-Scale Nanofiber Manufacturing| Cascadedimmunotherapywith implantable dual-drugdepotssequentiallyreleasingSTING agonists andapoptosis inducers

Li Mingqiang, Tao Yu, Xu Yanteng (Sun Yat-sen University) Nat. Commun.: Electrospinning-3D Printed Sandwich-like Dual-Drug Depot for Tumor Postoperative Eradication via Cascaded Immunotherapy

Surgical resection is an effective treatment for solid tumors, but positive margins often lead to recurrence and metastasis. Postoperative chemotherapy is commonly used but has limited efficacy and significant side effects. Some chemotherapeutic drugs can induce immunogenic cell death, initiating antitumor immune responses and providing strategies for immunotherapy. However, this alone is insufficient to eradicate tumors. Therefore, developing new postoperative adjuvant therapies to enhance antitumor immunity and inhibit recurrence/metastasis remains a clinical challenge.

Activating the STING-IFNβ pathway in tumor cells or antigen-presenting cells (APCs) can significantly enhance immune-mediated tumor killing. However, classical nucleotide STING agonists face clinical limitations due to poor cell membrane permeability and sensitivity to phosphodiesterases. Recent studies show that non-nucleotide STING agonist MSA-2 exhibits higher in vivo stability, better cellular uptake, and lower side effects. Nevertheless, like most STING agonists, MSA-2’s duration is limited by rapid lysosomal degradation of STING. While frequent dosing partially alleviates this, it compromises patient compliance and increases infection risks.

Recently, the research team of Li Mingqiang, Tao Yu, and Xu Yanteng from the Nanomedicine Center of the Third Affiliated Hospital of Sun Yat-sen University, in collaboration with He Weiling from Xiamen University, published their latest research titled "Cascaded immunotherapy with implantable dual-drug depots sequentially releasing STING agonists and apoptosis inducers" in Nature Communications. The researchers innovatively designed an implantable sandwich-like dual-drug depot (MS-DF-MS) combining electrospinning and 3D-printed hydrogel scaffolds.The MS-DF-MS integrates chemotherapy and immunotherapy, inducing persistent and efficient anti-tumor immune responses when implanted postoperatively through cascading self-reinforcing synergistic effects, effectively inhibiting tumor recurrence and metastasis (see Figure 1). 

Figure 1: Schematic diagram of the research.

 In this electrospun-3D printed hydrogel scaffold sandwich-like dual-drug depot, MSA-2 is loaded in the outer 3D-printed hydrogel scaffold layer (MS), while the chemotherapeutic drug DOX is encapsulated in the inner PLGA electrospun layer (DF). This design achieves long-term sustained release of both drugs at the residual tumor site.Due to the physical barrier effect provided by the outer scaffold and differences in drug solubility, MSA-2 is released before DOX, ensuring therapeutic timing (see Figure 2).

Figure 2: Properties of the electrospun-3D printed hydrogel scaffold sandwich-like dual-drug depot.

Figure 3: The electrospun-3D printed hydrogel scaffold sandwich-like dual-drug depot induces long-term immune-mediated antitumor effects against postoperative recurrence and metastasis.

The researchers innovatively revealed that prioritized MSA-2 release effectively activates the STING-IFNβ pathway in tumor cells and APCs, triggering endoplasmic reticulum stress-mediated immunogenic apoptosis. Subsequently released DOX not only enhances this apoptotic process, releasing abundant tumor-associated antigens, but also causes mitochondrial damage, releasing endogenous dsDNA that further activates the STING-IFNβ pathway.The key finding is that the MS-DF-MS system prevents STING degradation by promoting microtubule depolymerization, ensuring long-term activation of the STING-IFNβ pathway and overcoming limitations of single therapies. This dual-drug depot system, implanted after tumor resection, achieves sequential sustained release of STING agonists and immunogenic apoptosis inducers, significantly enhancing immunotherapy efficacy through cascading self-reinforcing effects (see Figure 7). This study provides a novel and highly effective therapeutic strategy for inhibiting postoperative tumor recurrence and metastasis, demonstrating great potential.