Immune checkpoint blockade (ICB) therapies targeting programmed cell death protein 1/programmed cell death ligand 1 (PD-1/ PD-L1) or cytotoxic T lymphocyte antigen 4 (CTLA-4) have been a revolutionary breakthrough in some solid tumors, such as head and neck squamous cell carcinoma (HNSCC) and melanoma [1], [2], [3], [4], [5]. Although some immunosuppressants have been approved for clinical trials, only a small number of patients have benefited from them, owing to the poor heterogeneity of tumor antigens, insufficient infiltration of immune cells, and the inhibitory effects of immunosuppressive cells from the tumor microenvironment (TME) [6], [7], [8], [9]. In addition to the search for new immune checkpoints, current research has focused on enhancing the efficacy of ICB therapies through combination drug strategies or material-based delivery methods [10,11]. Accumulated evidence already suggests that the efficacy of ICB therapy is related to the immune phenotype of the tumor. Hot tumors with significant T cell infiltration have a higher response rate to ICB therapy than cold tumors without T cell penetration [12], [13], [14]. Thus, new strategies should be developed to transform cold tumors into hot tumors for efficient cancer immunotherapy.

As pivotal secondary immune organs, lymph nodes maintain a physical structure that functions as a scaffold, positioning leukocytes for efficient immune surveillance and peripheral tolerance [15,16]. Particularly, tumor draining lymph nodes (TdLN) are closely related to the genesis and progression of malignant tumors. For certain tumors, such as breast cancer and melanoma, the condition of lymphatic drainage directly affects patient survival rate and long-term prognosis [17]. During the early stages of tumor development, the TdLN exhibits an anti-metastatic phenotype. However, with extensive infiltration of tumor cells, the structure of TdLN undergoes gradual deterioration, resulting in a pro-tumor metastatic phenotype [18]. In a recent study involving HNSCC patients, ICB therapy was observed to impede the differentiation of progenitor exhausted CD8+ T cells (Tpex) into terminally exhausted cells (Tex-term) in TdLN. This suggests that lymph node-focused immunotherapy may be critical in tumor therapy [19], [20], [21]. Despite this, current tumor therapy is still primarily oriented towards systemic administration or intra tumor administration, thereby overlooking lymph node regulation as a potentially influential factor in enhancing immunotherapy.

TEM cells can be differentiated from effector T cells (TCM), or directly differentiated from naive T cells after stimulation. They mainly migrate to peripheral tissues and produce immune effects immediately after being stimulated by antigens [22]. Although TEM cells maintain immune memory for a short period of time and mainly play a role in the first line of immune defense, they can characteristically express some chemokine receptors and adhesion molecules. This unique feature facilitates their homing to tumor tissues. When exposed to antigens, these cells swiftly initiate effector functions after reactivation [23,24]. Currently, most of the research on TEM cells is focused on mechanistic studies and has no direct application to tumor therapy. In this study, we developed an innovative approach to boost antitumor immune responses by leveraging TEM cells and PD-1 inhibitor (aPD-1) in conjunction with artificial lymph nodes. Specifically, TEM cells and aPD-1were loaded into an injectable thermosensitive F127 hydrogel. This system simultaneously targets TdLN and tumor, consistently supplying TEM cells to the TdLN and tumor immune microenvironment. This also can be combined with aPD-1 therapy to augment the efficacy of ICB therapy (Fig. 1). Our findings unveil the feasibility of lymph node reconstruction synergism with drug delivery and provide a promising new strategy to enhance the effect of immunotherapy.