TiSe2-mediated sonodynamic and checkpoint blockade combined immunotherapy in hypoxic pancreatic cancer

Abstract

Background Pancreatic cancer remains among the most prevalent and aggressive forms of cancer. While immunotherapeutic treatment strategies have shown some promise in affected patients, the benefits of these interventions have been limited by insufficient tumor infiltration by activated T cells. Results Here, Titanium diselenide (TiSe2) nanosheets were synthesized with good stability. When exposed to ultrasound (US), the TiSe2 nanosheets served as a reliable nano-sensitizer capable of inducing large amounts of reactive oxygen species (ROS) mediating sonodynamic therapy (SDT) under hypoxic and normoxic conditions. The tumor-released TAAs induced by TiSe2 nanosheet-mediated SDT promoted immunogenic cell death (ICD) conducive to the maturation of dendritic cells (DCs), and cytokine secretion and the subsequent activation and infiltration of T cells into the tumor. Combining TiSe2-mediated SDT with anti-PD-1 immune checkpoint blockade treatment led to the efficient suppression of the growth of both primary tumor and distant tumor, while simultaneously preventing lung metastasis. These improved immunotherapeutic and anti-metastatic outcomes were associated with activated systematic antitumor immune responses, including the higher levels of DC maturation and cytokine secretion, the increased levels of CD8+ T cells and the decreased levels of Treg cells infiltrated in tumors. Conclusion TiSe2 can be used as a sonosensitizer with good efficacy and high safety to mediate efficient SDT. The combination treatment strategy comprised of TiSe2-mediated SDT and PD-1 blockade activate anti-tumor immune responses effectively thorough inducing ICD, resulting in the inhibition the growth and metastasis of tumor. The combination therapy holds promise as a novel immunotherapy-based intervention strategy for pancreatic cancer patients.

Recent advances in sonodynamic therapy strategies for pancreatic cancer

“…It causes loosening of the tumor's peripheral matrix, facilitating the accumulation and penetration of sonosensitizers (Figure 1). This strategy demonstrates the capability of deep penetration, leading to loosening effects in the tumor's surrounding matrix and thereby facilitating the penetration and accumulation of sonosensitizers (L. Chen, Xue, et al, 2022). Sheng et al developed a nanodrop based on photo responsive perfluoropropane (PFP).…”

Four Ounces Can Move a Thousand Pounds: The Enormous Value of Nanomaterials in Tumor Immunotherapy

“…Titanium diselenide (TiSe 2 ), a 2D transition metal dihalide (TMDC), is widely used for its superior photoresponse performance. Titanium diselenide (TiSe 2 ) nanosheets were physically fabricated by Xu's research team [ 297 ] to induce large amounts of ROS to enhance SDT's effects in a US environment. In in vitro experiments, significant CRT exposure and nuclear HMGB1 release were seen in cancer cells after TiSe 2 nanosheet and US treatment, supporting the assertion that TiSe 2 induces ICD.…”

Tumor Microenvironment‐Related Sonodynamic Therapy Mediates Tumor Therapy

“…Damaged cells can release TAAs to the TME and induce long‐term systemic antitumor immunity. [ 111 ] SDT leads to the maturation of antitumor immune cells, such as DCs and NKs and reverses the immunosuppressive state of the TME ( Table 5 ). Therefore, SDT combined with ICB treatment of tumors can effectively improve the tumor immune environment and promote the ICD of tumor cells, making it the leading treatment regimen for inducing systemic antitumor immunity.…”

“…[101][102][103] The interaction between tumor cells and immune cells in the TME determines the immune state of the TME during tumor growth. [104] In the early stage of tumor growth, effector T cells (including the cluster of differentiation (CD8 + T cells), cytotoxic T cells, and effector CD4 + T cells), macrophage phenotype 1 (M1), and NK cells can cooperatively inhibit the occurrence Induce ICD Promote the maturation of DCs Zr-TCPP(TPP)/R837@M, PMPS NDs, AMR-MOF@AuPt [112,198,199] Promote the maturation of DCs, combined ICB Ru-TePt@siRNA-MVs, CPDA@PFH [113,114] Promote the maturation of DCs and NKs 195/Ce6-NBs [200] Promote the maturation of DCs, reduce Tregs cTiSe 2 NS, QDs [111,201] Combined ICB, and catalytic CDT, relieve hypoxia IRO@FA NP [202] Combined chemotherapy Doxo [203] Hyp [204] TAMs related Promote the transformation of M2 into M1, promote the maturation of DCs M1/IR780@PLGA [205] Targeted removal of M2, vascular normalization, and relief hypoxia M-H@lip-ZA [206] and growth of the tumor, and the TME shows a state of immune promotion. With the development of cancer, in the late stage of tumor growth, the TME mainly contains Tregs, M2 macrophages, and immature DCs, showing a tumor-promoting effect, and the TME presents an immunosuppressive state.…”