Harnessing innate immune pathways for therapeutic advancement in cancer

Abstract

The innate immune pathway is receiving increasing attention in cancer therapy. This pathway is ubiquitous across various cell types, not only in innate immune cells but also in adaptive immune cells, tumor cells, and stromal cells. Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment (TME) and improved tumor prognosis in preclinical studies. However, to date, the clinical success of drugs targeting the innate immune pathway remains limited. Interestingly, recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression. The uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation. In this review, we observe that the role of the innate immune pathway demonstrates heterogeneity, linked to the tumor development stage, pathway status, and specific cell types. We propose that within the TME, the innate immune pathway exhibits multidimensional diversity. This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks. The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways. Refining our understanding of the tumor's innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinical application.

Fig. 1

Tumor immune microenvironment. The TME mainly includes monocyte-derived macrophages (MDMs),^, tissue-derived macrophages (TRMs), dendritic cells (DCs), CD8⁺T lymphocytes (CTLs), CD4⁺ T lymphocytes,^, tumor-associated neutrophils (TANs), myeloid-derived immunosuppressive cells (MDSCs), and natural killer cells (NKCs). Cells in the tumor immune microenvironment have pro-tumor (purple) and anti-tumor (red) effects. The TME induces immune cells’ pro-tumor differentiation or polarization through various pathways. The abnormal microenvironment of a tumor (black text in the tumor’s center), along with factors (purple) secreted by the tumor itself, can induce cells within this environment to undergo differentiation or polarization towards a pro-tumor phenotype, or experience exhaustion of their anti-tumor functions. However, there are cytokines (red) that have the potential to overcome or reverse these pro-tumor phenotypes. Created with BioRender.com

Fig. 2

Innate immune pathways in the TME. a Sources of initiating factors for the activation of innate immune pathways. Under environmental stressors such as drugs, immune cytotoxic cells, and hypoxia, tumor cells undergo leakage or cell death, leading to the release of DAMPs into the TME. These DAMPs are sensed by PRRs in various cell types within the TME, thereby activating innate immune pathways. In this process, APCs can also directly engulf tumor cells, promoting the generation of DAMPs. b Signaling Pathways of Innate Immunity. Innate immune pathways are ubiquitously present in various cell types and are activated by components in the TME. This is primarily driven through three key steps: receptor sensing, signal transduction through adapter molecules, and the initiation of immune-related molecular transcription by transcription factors, thereby modulating the TME. Created with BioRender.com

Fig. 3

Signaling function of the cGAS-STING pathway. Upon activation, STING primarily exerts its effects through four major pathways. (1) inducing senescence or prompting surrounding cells to eliminate aberrant cells by releasing type I IFN and cytokines; (2) activating pyroptosis via NLRP3; (3) inducing cell death through autophagy; and (4) activating apoptosis. Furthermore, cGAMP can also propagate within the TME, mediating the activation of STING in surrounding cells. Created with BioRender.com

Fig. 4

Anti-tumor cell interaction network following activation of the cGAS-STING pathway. The red arrows represent the promotion while the blue arrows represent the inhibition. Created with BioRender.com

Fig. 5

Timeline of the milestones regarding the research on the innate immune pathway. Since the proposal of the PRRs concept in 1989, the TLRs pathway, NLRs pathway, RLRs pathway, and cGAS-STING pathway have been successively discovered and associated with oncology and cancer treatment. Created with BioRender.com

Fig. 6

Innate immune sensors and their pathways in the nucleus. (1) hnRNPA2B1 recognition of dsDNA in the nucleus is followed by JMJD6-induced demethylation, promoting its translocation to the cytoplasm. There, hnRNPA2B1 is recruited to STING, triggering downstream activation. (2) SAFA identifies dsRNA and homodimerizes to bind to multiple SAFA binding sequences in the IFNB1 enhancer, promoting the transcription of type I IFNs. (3) Upon recognizing dsDNA, IFI16 relocates to the cytoplasm to activate the STING pathway. It also recruits ASC and caspase-1 to form inflammasomes. (4) ZBP1 detects Z-RNAs, activating RIPK3. Subsequent RIPK3 activation induces cell apoptosis and phosphorylates MLKL. Phosphorylated MLKL disrupts nuclear and cellular membranes, leading to necroptosis. Created with BioRender.com

Fig. 7

Obstacles and solutions for tumor treatment with innate immune pathway agonists. a Adjusting dosage and delivery methods to achieve optimal therapeutic effects. b Selectively targeting cell types that possess anti-tumor activities upon activation of innate immune pathways. c Overcoming immune escape caused by bypass activation of agonists through combination therapies. d Correcting aberrant innate immune pathways. Created with BioRender.com

Fig. 8

Precision treatment with innate immune pathway agonists. (1) Rational drug dosing and development of high-potency drugs. (2) Appropriate dosing regimens to overcome immune tolerance. (3) Efficient and precise delivery methods. (4) Selective targeting of specific cell types. (5) Tumor type and anatomical location. (6) Molecular and biochemical characteristics of the tumor. (7) Patient characteristics, including gender, age, health status, and medical history. (8) Patient’s genetic traits, especially genetic polymorphisms related to the innate immune pathway. (9) Correction of aberrant innate immune pathways. (10) Combination therapies to amplify therapeutic effects and avoid immune evasion. Created with BioRender.com

Fig. 9

Targeted cell type-specific plasticity in the innate immune pathway network. In the tumor microenvironment, various types of cells construct a complex intercellular interaction network. These diverse cells exhibit heterogeneous innate immune pathways, with some cells predominantly featuring tumor-promoting pathways, while others are dominated by tumor-suppressing pathways. Additionally, the tumor background participates in shaping these pathways, meaning the same cell type can exhibit different innate immune pathway configurations in various microecological niches. Different targeting strategies may lead to distinct clinical outcomes: (1) Non-selective activation of innate immune pathways may cause a shift towards a tumor-promoting environment due to the dominance of immunosuppressive interactions; (2) A combination of non-selective innate immune pathway activators and tumor-promoting alternative pathway inhibitors can mediate changes across the entire network, potentially exerting anti-tumor effects; and (3) Cell type-specific innate immune pathway activators may induce localized anti-tumor actions. Created with BioRender.com