Hydrogel/nano-immunostimulant composite mitigates surgery-exacerbated immunosuppression for durable postsurgical adjuvant treatment of high-propensity lymph node-metastatic tumors.

The development of effective postsurgical adjuvant treatments for tumors, particularly high-propensity lymph node-metastatic tumors (LNMTs), remains a significant challenge. Our study elucidates the critical role of surgery in exacerbating immunosuppression, thereby contributing to the high postsurgical recurrence rate observed in high-propensity LNMTs. To address this issue, we developed an inflammation-immunomodulatory hydrogel/nano-immunostimulant composite system (PLA-MnO Gel) for durable postsurgical adjuvant treatment of high-propensity LNMTs. Upon implantation at the surgical site, the poly(α-lipoic acid) hydrogel (PLA Gel) effectively alleviates surgery-induced postsurgical local acute inflammation (PLAI), restoring the exacerbated immunosuppressive state to a pre-surgical mild immunosuppressive condition, especially within metastatic lymph nodes (LNs). Simultaneously, MnO nano-immunostimulants released from the PLA hydrogel specifically activate immune responses in metastatic LNs, further elevating immune levels beyond baseline. Our findings clearly demonstrate that PLA-MnO Gel can durably prevent postsurgical recurrence of lymph node-metastatic melanoma (LNMM) and lymph node-metastatic breast cancer (LNMBC), highlighting its potential in mitigating surgery-exacerbated immunosuppression and thereby enhancing therapeutic outcomes for high-propensity LNMTs.