The team of Associate Professor Song Yanzhi and Professor Deng Yihui from the School of Pharmacy of Shenyang Pharmaceutical University published a paper in the 1st issue of Acta Pharmaceutica Sinica B in 2023. They used sialic acid-mediated photochemotherapy to eliminate the impact of immune aging on anti-tumor treatment in elderly mice, induced tumor shedding in some mice, and the mice cured within 59 days did not show in situ tumor recurrence and distant metastasis.

The 21st century is an era of aging population, and diseases related to the elderly are becoming increasingly prominent. After the outbreak of COVID-19, the susceptibility and lower recovery ability of the elderly led to high infection and mortality rates. In April 2020, Nature announced the addition of Nature Aging to promote exchanges between experts in this field. Aging causes the immune system to gradually undergo a series of degenerative changes under the long-term combined action of multiple factors. This phenomenon is called immunosenescence. The aging of T lymphocytes is the main cause of immunosenescence.

To date, most studies on immunosenescence have focused on the aging of the immune system itself and the underlying mechanisms. However, the impact of immunosenescence on the treatment of certain age-related diseases, especially tumors, remains unexplored. In preclinical anti-tumor therapy studies, 4- to 8-week-old mice (equivalent to 1- to 16-year-old humans) are used as experimental animals; however, this age does not match the age of clinical patients. Clinical data show that the peak incidence of human cancer is 50 to 70 years old. Immunosenescence greatly affects the distribution of nanomedicines that are closely related to the immune system.

Over the past 20 years, the research group has been studying the close relationship between the immune system and nanomedicine. They systematically studied sialic acid (SA)-modified nanoparticles (NPs) and established a sialic acid-mediated neutrophil drug delivery system. We found that the accumulation of SA-modified NPs in tumors was increased by increasing the infiltration of neutrophils into tumors through photodynamic/photothermodynamic therapy. Doxorubicin (DOX) liposomes modified with sialic acid cholesterol conjugate (SA-CH) can induce the expression of calreticulin on the surface of tumor cells, increase the secretion of high-mobility group protein B1, and promote the release of ATP. In this way, dendritic cells can effectively recognize and phagocytize tumor cells and present tumor antigens. However, the above research results were obtained through 4-8 week-old mice, without considering the potential impact of immune aging on anti-tumor therapy. For this reason, the authors designed relevant experiments to investigate the relationship between immune aging and anti-tumor therapy.

In this study, the authors found that the number of CD8+T cells and neutrophils in 16-month-old mice was significantly reduced, which inferred that 16-month-old mice had immune senescence. During the anti-tumor treatment of 2-, 8-, and 16-month-old mice, sialic acid-modified indocyanine green-loaded liposomes (SL-ICG) increased the infiltration of neutrophils and CD8+ T cells in the tumor, causing scabs to appear at the tumor site of some mice; however, the aging of CD8+ T cells in the cured mice led to tumor recurrence in situ and distant metastasis, the extent of which varied with the age of the mice. Sialic acid-modified doxorubicin-loaded liposomes (SL-DOX) can induce immunogenic cell death (ICD) of tumor cells; however, the aging of neutrophils severely hindered the neutrophil drug delivery system in 16-month-old mice. Sialic acid-modified co-loaded liposomes (SL-Co) promoted the infiltration of CD8+ T cells and neutrophils into the tumor, increased the accumulation of drugs at the tumor site, and eliminated the effect of immune senescence on anti-tumor treatment in 16-month-old mice.

                                   

Sialic acid-mediated photochemotherapy enhances infiltration of CD8+ T cells from tumor-draining lymph nodes into tumors of immunosenescent mice Dezhi Sui, Changzhi Li, Xueying Tang, Xianmin Meng, Junqiang Ding, Qiongfen Yang, Zhaowei Qi, Xinrong Liu, Yihui Deng, Yanzhi Song*Acta Pharm Sin B 2023;13(1):425-439