An “innate immunity + local immune activation” combination strategy: Systemic IFN-I and topical TLR7/8-based antitumor immunotherapy strategy —a perspective from Bo Xiao and Chenghui Wang's group at University of Electronic Science and Technology of

Research background

Distant metastasis and recurrence remain major obstacles limiting the long-term efficacy of immunotherapy for solid tumors, particularly in highly aggressive cancers, such as malignant melanoma. Dendritic cells (DCs), as a bridge between innate and adaptive immunity, play a decisive role in the strength and persistence of antitumor immune responses. In recent years, TLR7/8-targeting immune agonists (e.g., imiquimod, IMQ) have been widely applied in local immunotherapy. However, due to poor tissue penetration and significant systemic toxicity, their clinical application is still limited to superficial tumors. Studies have shown that the combination of systemic type I interferons (IFN-I) and local TLR7/8 agonists can significantly enhance DC activation and inhibit metastatic tumors. This commentary delves into the synergistic activation mechanism of plasmacytoid and conventional dendritic cells (pDC-cDC), analyzes their multilayered roles in antitumor immunity, and discusses their translational potential when combined with immune checkpoint blockade therapy.

Research progress

Focusing on the “Synergistic immune activation mechanism of IFN-I and TLR7/8,” this article dissects the key immunological processes underlying the combination of systemic IFN-I with topical IMQ in suppressing metastatic tumors. The study reveals that oral administration of IMQ activates plasmacytoid dendritic cells (pDCs), inducing systemic IFN-I production. This, in turn, upregulates TLR7 expression in conventional DCs (cDCs) within the tumor microenvironment, making them responsive to topical IMQ. This leads to c-Jun–dependent IL-12 secretion and CCL2-mediated pDC recruitment, ultimately resulting in local tumor necrosis and activation of long-range immune memory. This strategy enables early innate immune control in T cell–deficient environments and later induces CD8⁺ T cell responses. Combined with PD-1 antibodies, it can completely suppress tumor growth. Furthermore, the article highlights that systemic IFN-I can replace oral IMQ and, when used with topical IMQ, produce equivalent antitumor effect, thereby expanding clinical applicability. To address the systemic toxicity of IMQ and IFN-I, the study proposes 3 forward-looking strategies: (1) Micro-nano delivery platforms: develop micro- and nano-scale delivery systems (e.g., liposomes, micelles, and microspheres) to target tumors and lymphoid tissues, thereby reducing systemic inflammatory risk. (2) Smart modification: use pH-sensitive carriers or ligand-functionalized techniques to prolong drug half-life and enhance cDC-specific uptake. (3) Combination delivery: promote co-delivery of IMQ/IFN-I with immune checkpoint inhibitors, tumor antigens, or chemotherapy agents to enhance immune activation and reduce dosing requirements (Figure 1).

Future Outlook

Despite the above promising findings, clinical translation of these strategies faces multiple challenges, including dosage optimization, delivery vehicle safety, and large-scale production. The paper outlines 3 frontier directions.

1. Precision optimization of micro-nano delivery systems: explore FDA-approved materials and efficient fabrication strategies (e.g., microfluidics) to accelerate clinical translation.
2. Targeted activation of DC subsets: utilize single-cell sequencing and genetic modification tools to dissect key molecular networks in pDC-cDC interactions and refine immune synergy strategies.
3. Personalized combination therapy design: tailor IMQ/IFN-I combinations with immune checkpoint inhibitors, vaccines, or cell therapies based on patients' tumor immune microenvironment profiles.

These innovations will drive the clinical translation of innate-adaptive immune synergy therapies and provide safer, more effective treatment strategies for malignant tumors.

Sources: https://spj.science.org/doi/10.34133/research.0739