Research Insight - An Epigenetic Nano-Agonist Promotes T Cell Priming, Recruitment, and Reinvigoration in PD-L1–Resistant Tumors

Recently, Associate Researcher Xiaojiao Li from the First Affiliated Hospital of Xi’an Jiaotong University, together with Professor Jiye Zhang and Assistant Professor Jia Ma from the School of Pharmacy, Xi’an Jiaotong University, has made new progress in the field of immunotherapy for PD-L1–resistant tumors. The related findings have been published in the internationally renowned journal *Advanced Materials* (IF = 26.8, top-tier journal).

In recent years, immune checkpoint inhibitors (e.g., PD-1/PD-L1 antibodies) have achieved breakthrough advances in the treatment of multiple cancers. However, resistance to PD-L1 blockade has emerged as an increasingly prominent clinical challenge. The core issue lies in the tumor microenvironment, where T cell priming efficiency is insufficient, recruitment is limited, and post-activation functional exhaustion occurs. T cell priming depends on the maturation of dendritic cells (DCs), and activation of the cGAS–STING signaling pathway is critical for DC maturation. T cell recruitment is primarily regulated by CXCR3-mediated chemotactic migration. Conventional therapies such as radiotherapy and chemotherapy are often accompanied by immune cell damage, further weakening the efficacy of immunotherapy. In addition, upregulation of alternative immune checkpoints, such as poliovirus receptor (PVR), in PD-L1–resistant tumors suppresses immune responses by interacting with TIGIT on T cells and natural killer (NK) cells, thereby exacerbating T cell exhaustion. Therefore, developing an innovative strategy capable of simultaneously addressing T cell priming, recruitment, and activation has become a critical need for overcoming therapeutic bottlenecks in PD-L1–resistant tumors.

Based on this rationale, the present study successfully constructed a pH-responsive charge-reversal nanoplatform (DPM@iCARM1@siPVR), which enables the co-delivery of a CARM1 inhibitor (iCARM1) and PVR-targeting small interfering RNA (siPVR), offering a novel multi-level strategy to activate T cell responses in PD-L1–resistant tumors. Upon entry into the tumor microenvironment, pH-triggered charge reversal enhances cellular uptake. The released iCARM1 epigenetically activates the cGAS–STING signaling pathway in tumor cells, promoting DC maturation to enhance T cell priming, while upregulating CXCR3 expression in T cells to facilitate their recruitment. Meanwhile, siPVR silences the PVR gene, disrupting the PVR–TIGIT interaction and thereby restoring T cell activation. In two PD-L1–resistant tumor models (4T1 and CT26), this nanoformulation significantly inhibited tumor growth, metastasis, and postoperative recurrence, prolonged survival in tumor-bearing mice, and induced long-term immune memory to resist tumor rechallenge. Moreover, when combined with anti–PD-L1 therapy, it exhibited a synergistic therapeutic effect. By precisely regulating key steps of T cell responses, this strategy effectively remodels the immunosuppressive tumor microenvironment and provides a promising new direction with strong clinical translational potential for the treatment of PD-L1–resistant tumors.

In the study, to evaluate the in vivo antitumor efficacy of the epigenetic nano-agonist (DPM@iCARM1@siPVR), an AniView multimodal in vivo imaging system (Guangzhou Biolight Biotechnology Co., Ltd.) was employed for monitoring. As shown in Figure 1, compared with the control group (saline), free iCARM1 group, and DPM@iCARM1 group, the DPM@iCARM1@siPVR group exhibited the weakest tumor bioluminescence signals, with slow growth throughout the observation period, directly demonstrating that this pH-responsive charge-reversal nanoplatform, through co-delivery of iCARM1 and siPVR, more effectively suppresses the growth of PD-L1–resistant tumors. As shown in Figure 2, the control group, empty vector group (DPM), free iCARM1 group, and DPM@iCARM1 group all exhibited varying degrees of postoperative recurrence and metastasis, whereas none of the eight mice in the DPM@iCARM1@siPVR group showed recurrence or metastasis, confirming its potent inhibitory effect on postoperative relapse and metastasis of PD-L1–resistant tumors. As shown in Figure 3, all mice (100%) in the control group developed rapid tumor growth, whereas approximately half of the mice in the DPM@iCARM1@siPVR group did not develop detectable tumors. The remaining mice exhibited significantly reduced bioluminescence signals and markedly smaller tumor volumes compared to controls, clearly indicating the induction of long-term immune protection.

Article link:

https://doi.org/10.1002/adma.202502800