Immunotherapy targeting the PD-1/PD-L1 axis has emerged as a transformative strategy in cancer treatment [1]. By reinvigorating exhausted T-cells, this approach restores their capacity to recognize and eliminate malignant cells. However, the efficacy of PD-1/PD-L1 blockade is frequently limited by the immunosuppressive properties of the tumor microenvironment (TME) [2]. This inherent complexity manifests in two major limitations: primary resistance, where certain patients fail to respond initially, and acquired resistance, wherein responders progressively lose therapeutic benefits over time. Collectively, these challenges result in the relatively low clinical success rate of PD-1/PD-L1 monotherapy, with only approximately 20 % of patients achieving durable responses [3]. To address these obstacles, the identification and development of next-generation immunomodulatory targets, preferably those that synergize with PD-1/PD-L1 inhibition while ensuring safety, has become a critical focus in oncology research. Such combinatorial approaches hold promise for enhancing anti-tumor immunity and expanding the patient population eligible for effective immunotherapy [4].

Dual-target inhibitors can address the issues of drug resistance and insufficient efficacy caused by single-target inhibition by simultaneously targeting multiple pathways within the tumor microenvironment, thereby demonstrating significant potential for drug development [5]. Leveraging the advantages of multi-target strategies, we have previously designed and reported several dual-target inhibitors, including PD-L1/CXCL12 [6], PD-L1/HDAC3 [7], PD-L1/HDAC6 [8], and PD-L1/EGFR [9] combinations. These studies collectively demonstrate that the dual-targeting strategy can substantially enhance the anti-tumor efficacy of immunotherapy. Furthermore, there have been reports on various dual-acting agents targeting PD-L1/VISTA [10] and PD-L1/PARP7 [11], which provide evidence supporting the rational design of PD-L1-based dual-target inhibitors (Fig. 1).

NAMPT, a rate-limiting enzyme in NAD+ synthesis, is highly expressed in various tumors and contributes to cancer progression [12]. Studies have consistently shown that NAMPT plays a critical role in tumor immune evasion and drives resistance to anti-PD-L1/PD-1 therapy (Fig. 2) [13]. For malignancies exhibiting resistance to anti-PD-1/PD-L1 immune checkpoint blockade therapy, pharmacological inhibition of NAMPT demonstrates significant potential in potentiating immunotherapeutic response. This preclinical evidence establishes a mechanistic rationale for developing combination therapeutic strategies targeting both PD-L1 signaling and NAD+ biosynthesis pathways [14].

Through systematic co-expression profiling of PD-L1 and NAMPT utilizing pan-cancer transcriptomic data from the Cancer Genome Atlas (TCGA), we observed consistent co-upregulation of these two molecular targets across multiple malignancies, particularly in lung cancer and cutaneous melanoma. Intriguingly, Spearman correlation analysis revealed a significant positive transcriptional correlation between NAMPT and PD-L1, suggesting their functional interconnection within the immunosuppressive TME. This conserved co-expression pattern implies the existence of a NAMPT-PD-L1 regulatory axis that may synergistically mediate metabolic reprogramming and immune evasion mechanisms in neoplastic tissues (Fig. 3).

Currently, dozens of NAMPT-based dual inhibitors have been reported, and the majority of which are progressing through various phases of preclinical evaluation or clinical trials (Fig. 4) [15]. These dual-target agents offer not only exceptional advantages in addressing the resistance and insufficient response rate issues of single-target drugs, but also circumvent drug interactions and heterogeneous pharmacokinetics problems when used in combination.

Mechanistically, PD-L1 and NAMPT play pivotal roles in tumor immune escape. Inhibition of the PD-1/PD-L1 axis enhances the cytotoxic activity of effector T cells against cancer cells, whereas blockade of the NAMPT target activates the tumor immune microenvironment, alleviates effector T cell immunosuppression, and augments the efficacy of immune checkpoint inhibitors as well as the host's tumor-eliminating capacity. Consequently, given the critical physiological functions of PD-L1 and NAMPT within the tumor immune microenvironment, this study designed and synthesized a series of dual-targeting inhibitors that simultaneously modulate PD-L1 and NAMPT, offering a novel approach and strategy for tumor immunotherapy as detailed below.