EDITORIAL: Innate Immune Pathways as Targets for Developing Therapeu9c Interven9on against Human Cancers

Fabio Grizzi^1*Miguel Martin-Perez²Geeta Rai³Abdullah Saeed⁴Ayush Raman⁵Devivasha Bordoloi⁶

• ¹Humanitas Research Hospital, Rozzano, Milan, Italy
• ²University of Barcelona, Barcelona, Catalonia, Spain
• ³Banaras Hindu University, Varanasi, Uttar Pradesh, India
• ⁴University of Michigan, Ann Arbor, Michigan, United States
• ⁵National Cancer Institute, NIH,, Bethesda,, United States
• ⁶Indian Institute of Science Education and Research, Bhopal, Bhopal, Madhya Pradesh, India

pathogens, ensuring a rapid response to infec9ons [1]. Unlike the adap9ve immune system, which requires 9me to develop a targeted response, the innate immune system provides a broad yet immediate defense against pathogens [2,3]. It detects pathogens using specialized receptors, processes the informa9on through signaling pathways, and then triggers a targeted response, including the ac9va9on of the inflammatory response. Inflamma9on occurs when innate immune cells recognize infec9on or 9ssue damage [4].The "innate immune pathway" is a_rac9ng growing interest in cancer treatment because of its broad expression across different cell types, such as immune, tumor, and stromal cells [5]. The innate immune pathway network varies across different cell types, being controlled by cell-specific regulatory mechanisms that result in diverse func9onal responses to iden9cal s9muli (Figure 1). This modula9on determines whether immune responses support or inhibit tumor growth. However, disturbances in intracellular signaling within immune cells, along with adap9ve changes in tumor cells in the microenvironment, frequently compromise innate immune pathways, hindering their proper func9on. Understanding and strategically modula9ng these pathways in the TME is essen9al for leveraging them in cancer therapy.The "danger theory", explains why strong immune responses arise despite the absence of microbial components [6]. In response to trauma, ischemia, and cellular damage or death, molecules that typically serve non-immunological func9ons within cells are released, secreted, or exposed on the cell surface, triggering an immune response independent of infec9on. These molecules, later iden9fied as damage-associated molecular pa_erns (DAMPs), are crucial in triggering innate immune responses and promo9ng the produc9on of pro-inflammatory cytokines and interferons (IFNs). Molecules such DAMPs, which s9mulate innate immune signaling, are abundant in the TME, reinforcing the therapeu9c poten9al of targe9ng these pathways [7]. DAMPs play a crucial role in ac9va9ng innate immune mechanisms in cancer. Among these, aberrant DNA recogni9on via the cGAS -STING pathway is par9cularly significant for detec9ng transformed cells, both under normal condi9ons and aeer cancer treatment [8]. Cyclic GMP-AMP (cGAMP) synthase (cGAS) func9ons as a cytosolic DNA sensor that ac9vates the s9mulator of interferon genes (STING) protein, ini9a9ng a defensive immunological ac9va9on against DNA-based pathogens and strengthening an9-cancer immune ac9vity [9,10]. The Toll-like receptors (TLRs) family are expressed across various immune cell types and recognize diverse pathogen-associated molecular pa_erns (PAMPs) and DAMPs, including DNA, RNA, and lipopolysaccharides (LPS). Tumor cells also express mul9ple TLRs, and their ac9va9on can autonomously trigger cell death through different pathways [11]. Ac9va9on of TLRs can reverse the immunosuppressive effects of tumor-associated cells by modula9ng metabolism, making them promising targets for cancer immunotherapy. The NOD-like receptor (NLR) pathway consists of cytosolic sensors called Nucleo9de Oligomeriza9on Domain (NOD)-like receptors, which are crucial for detec9ng infec9ons and controlling autoinflammatory responses. The RIG-I-like receptor (RLR) pathway comprises cytoplasmic sensors that recognize viral RNA, including Re9noic Acid-Inducible Gene 1 (RIG-I), Melanoma Differen9a9on-Associated Factor 5 (MDA5), and Laboratory of Gene9cs and Physiology 2 (LGP2) [12]. RLR ac9va9on primarily engages the NF-κB pathway and promotes apoptosis. These receptors also influence tumorigenesis, with studies showing that reduced RIG-I expression facilitates the development of hepatocellular carcinoma (HCC) [13]. Recently, several nuclear molecules have been iden9fied as "innate sensors" ac9va9ng the immune pathway. These include Z-DNA binding protein 1 (ZBP1), Scaffold-a_achment-factor A (SAFA) and Heterogeneous Nuclear Ribonucleoprotein A2B1 (hnRNPA2B1). Other key molecules include Interferon gamma-inducible protein 16 (IFI16) and Non-POU domain-containing octamerbinding protein (NONO). Although these targeted drugs have demonstrated significant efficacy in preclinical trials, their success in clinical senngs has been only marginal. Iden9fying the factors behind the inconsistent therapeu9c effec9veness of these targeted drugs is cri9cal and requires further inves9ga9on [14].This Research Topic explores recent advancements in innate immune signaling pathways that are related to both the protec9on and pathogenesis of human cancers. Technological advancements, new methodologies, and the development of novel knowledge and fundamental insights, alongside the explora9on of new targets and therapeu9cs, are expected to further strengthen ongoing research in this area. The collec9on presents a comprehensive selec9on of ar9cles that address the immunobiological relevance of innate immune pathways in the pathogenesis of various human cancer subtypes and the host immune response to cancer. It also highlights the therapeu9c poten9al of innate signaling-directed chemo-and immunotherapeu9c interven9ons in human cancers.Xue et al. [15] inves9gate the complex interplay of cGAS-STING signaling in chronic hepa99s, alcoholic liver disease (ALD), metabolic dysfunc9on-associated steato9c liver disease (MASLD), and HCC, discussing its poten9al as a therapeu9c target. Emerging evidence indicates that cGAS-STING signaling is crucial for maintaining liver homeostasis and contributes to the onset and course of various liver diseases. The authors offer a detailed analysis of the cGAS-STING pathway, with a focus on its signaling cascade and its involvement in several major liver diseases.In HCC, cGAS-STING-targeted strategies include nanomaterial-based delivery of STING agonists, combining radiofrequency abla9on or radiotherapy to enhance pathway ac9va9on. Modula9ng cGAS-STING may also offer treatment op9ons for chronic viral hepa99s, MASLD, and ALD by boos9ng an9viral defenses or reducing inflamma9on. This highlights the pathway's complex role in liver diseases and the need for further research to realize its therapeu9c poten9al.Growing evidence highlights the cGAS-STING pathway's key role in tumor immunity, with STING agonists enhancing immunotherapy efficacy and reducing resistance. However, this pathway can both support an9-tumor responses and promote immunosuppression. Immunosuppressive cells like M2 macrophages, myeloid-derived suppressor cells, and regulatory T cells in the TME contribute to tumor escape and limit immunotherapy success.Zhang et al. [16] offer an in-depth review of cGAS-STING ac9va9on, its immune func9ons, and its key role in immune evasion driven by the immunosuppressive TME. They also outline key immunotherapeu9c approaches linked to this pathway and discuss poten9al enhancements to improve their effec9veness, offering important insights for future clinical use.Recent studies highlight intra-tumoral delivery of TLR ligands as a promising way to trigger local immune responses and enhance an9tumor immunity. However, their rapid spread from the TME limits efficacy and raises toxicity concerns. Kim et al. [17] inves9gated intra-tumoral delivery of mRNA encoding UNE-C1, a TLR2/6 ligand recognized for its efficacy and low toxicity. Their findings demonstrate that UNE-C1 triggers immunogenic cell death through autocrine signaling, mediated by DAMP release via TLR2 ac9va9on. Sensi9vity to this effect depends on TLR2 and Fas-associated death domain expression in cancer cells. UNE-C1 also ac9vates dendri9c cells via TLR2, priming CD8 + T cells essen9al for tumor regression. These findings support intra-tumoral mRNA delivery of UNE-C1 as a promising an9tumor strategy.Once seen mainly as acute inflamma9on mediators, neutrophils were ini9ally overlooked in cancer.It is now clear they infiltrate the TME in large numbers as tumor-associated neutrophils (TANs), a diverse and adaptable immune subset. Rising interest in their roles has spurred research into TANtargeted therapies, though clinical transla9on remains challenging. Xiao et al. [18] reviewed TANrelated studies published between 2000 and 2024, using data from the Web of Science Core Collec9on. They conducted bibliometric analysis and visualiza9on with tools like Microsoe Excel, VOSviewer, CiteSpace, and R-bibliometrix. The analysis included 788 publica9ons by 5,291 authors from 1,000 ins9tu9ons in 58 countries/regions, published across 324 journals.While China contributed the largest number of publica9ons and hosted the top 10 ins9tu9ons, the United States emerged as the leader in terms of high-quality publica9ons and as a global center for collabora9on. The analysis suggests that future research will likely concentrate on TAN heterogeneity, neutrophil extracellular traps, TAN interac9ons with other immune cells, and immunotherapy. This thorough bibliometric and visual analysis offers a detailed overview of the present state and conceptual founda9on of TAN research, providing fresh insights for future inves9ga9ons. Iden9fying dis9nct TAN subpopula9ons and precisely targe9ng key pro-tumor and an9-tumor groups presents significant poten9al for developing TAN-targeted immunotherapies.Bacillus Calme_e-Guérin (BCG) is the primary treatment for bladder cancer and is also used in melanoma immunotherapy [19]. It modifies the TME to trigger a strong an9tumor response, though the immune mechanisms are not fully understood.The immune profile of B16-F10 murine melanoma cells was assessed by infec9ng them with BCG or s9mula9ng them with agonists for various innate immune pathways, including TLRs, inflammasome, cGAS-STING, and type I IFN. B16-F10 cells responded only to type I IFN agonists, unlike bone marrowderived macrophages (BMDMs), which produced high proinflammatory cytokines. Borges et al. [20] confirmed that BCG can infect B16-F10 cells, which then ac9vate macrophages and spleen cells from mice in co-culture. They also created a subcutaneous B16-F10 melanoma model for intratumoral BCG treatment, comparing wild-type mice with various knockout models, including TLR2-/-, TLR3-/-, TLR4-/-, TLR7-/-, TLR3/7/9-/-, caspase 1-/-, caspase 11-/-, IL-1R-/-, cGAS-/-, STING-/-, IFNAR-/-, and MyD88-/-. In vivo findings showed that MyD88 signaling is crucial for BCG immunotherapy to control melanoma in mice. BCG failed to induce cytokine produc9on in co-culture with B16-F10, BMDMs, or spleen cells from MyD88-/-mice, compared to wild-type controls. It also did not recruit inflammatory cells to the TME in MyD88-/-mice, impairing tumor control and IFN-γ produc9on by T cells. Thus, MyD88 is pivotal for both innate and adap9ve immune responses to BCG, enabling an effec9ve an9tumor response.Glioma is a malignant tumor that affects the central nervous system (CNS), and currently, effec9ve treatment op9ons remain scarce. Recent discoveries of cranial-meningeal channels and intracranial lympha9c vessels have provided new insights into the origins of neutrophils in the CNS. Neutrophils in the brain are thought to originate more from the skull and adjacent vertebral bone marrow.Recent discoveries of cranial-meningeal channels and intracranial lympha9c vessels have shed new light on the origin of neutrophils in the central nervous system [21]. It is now believed that neutrophils in the brain primarily originate from the bone marrow within the skull and adjacent vertebrae. Driven by chemokines, these cells traverse the blood-brain barrier, infiltrate the brain parenchyma, and migrate to the glioma TME, where interac9ons with tumor cells trigger phenotypic changes. Sun et al. [21] provide a comprehensive review of the molecular mechanisms that govern neutrophil infiltra9on into the CNS from peripheral sources. Their work outlines the origin, func9ons, classifica9on, and poten9al therapeu9c targe9ng of neutrophils in the context of glioma.As key players in the immune system, neutrophils are gaining increasing recogni9on for their involvement in brain tumors. Further inves9ga9on into their role in cancer immunotherapy may open new avenues for developing more effec9ve treatment strategies for cancer pa9ents.Numerous agonists targe9ng the innate immune system have been proposed, with several in clinical trials showing therapeu9c poten9al. While research on the cGAS-STING pathway is s9ll early, ini9al findings suggest it may offer effec9ve and safe treatment op9ons. Poly-ICLC, a co-agonist of TLR3, RIG-I, and MDA5, has shown clinical benefit in several trials. Everson et al. [22] reported that autologous tumor lysate-pulsed dendri9c cell vaccina9on combined with a TLR agonist was safe and enhanced systemic immunity, marked by increased interferon expression and immune cell ac9va9on. Clinical studies u9lizing NLR agonists for tumor interven9ons, however, remain limited.It is also evident that DAMPs are ac9vators of the innate immune pathway, and therapies that increase DAMP produc9on not only enhance ac9va9on but also prolong its effect. These approaches can reduce the required dosage of ac9vators, minimizing adverse reac9ons. Addi9onally, the synergis9c impact of combining innate immune agonists with immune checkpoint inhibitors (ICBs) in cancer treatment is now well understood mechanis9cally. The ac9va9on of intrinsic immune pathways can trigger specific pro-tumoral mechanisms, which may reduce or even counteract the effects of immune pathway agonists. Since the discovery of innate immune pathways, our understanding has advanced considerably, driving numerous preclinical and clinical cancer treatment trials. Despite progress, milestones in the clinical use of innate immune pathway agonists remain elusive. When used therapeu9cally, innate immune pathway agonists exhibit varying pharmacological effects on the same system, depending on factors like potency, dosing schedule, and concentra9on. Overall, targe9ng these pathways to reshape the TME and enhance tumor outcomes remains a highly compelling area of research. Innate immune pathway agonists exhibit variable effects, influenced by factors like potency, dosing interval, and concentra9on. Targe9ng these pathways to reshape the TME and improve tumor prognosis is a promising area of research.It is now clear that further progress depends on cross-disciplinary collabora9on spanning molecular biology, systems biology, immunology, and oncology. AI-powered models built from such integrated data can improve drug efficacy predic9ons and speed up development. The tumor immune microenvironment (TME) includes macrophages, dendri9c cells, T lymphocytes, neutrophils, myeloid-derived suppressor cells, and natural killer cells, forming a network with both pro-and an9-tumor effects. The TME influences immune cell differen9a9on and polariza9on, oeen promo9ng a pro-tumor state. Cell-to-cell communica9on between the immune system and tumors shapes tumor development, progression, and treatment response (A). Stressors like drugs, immune cytotoxicity, and hypoxia cause tumor cell leakage or death, releasing DAMPs into the TME, detected by PRRs to ac9vate innate immune pathways (B). An9gen-presen9ng cells amplify DAMP produc9on by engulfing tumor cells. Analyzing innate immune pathways is vital for clinical cancer treatments, requiring an interdisciplinary approach and leveraging AI to enhance predic9ve modeling, improving drug efficacy and accelera9ng discovery (C).