Hypothetical Mechanisms of Immune Response Activation Under Profound Suppression

Research Article Immune activation through mimicry of physiological signals: A testable hypothesis on the restoration of surveillance in states of suppression Murad Novruzov a,* , Marziyya Mammadova b,c,d , Waseem Ullah Khan e , Ulkar Shiraliyeva f a Independent Biomedical Researcher, Baku, Azerbaijan b Azerbaijan State Advanced Training Institute for Doctors named after Aziz Aliyev, Baku, Azerbaijan c Ministry of Health of Azerbaijan, Azerbaijan d Azerbaijan Science and Health Initiatives (ASHI), Azerbaijan e National Institute of Health, Islamabad, Pakistan f Azerbaijan State Oil and Industry University, Baku, Azerbaijan ABSTRACT Profound immune suppression, manifested as anergy, secondary immune dysfunction, or exhaustion, leads to the collapse of immune surveillance in preclinical models of malignancy, sepsis, and chronic viral infection. Existing systemic immunostimulatory approaches are often unable to restore local immune competence without causing off-target inflammation or toxicity. We hypothesize that spatially confined immune reactivation can be achieved by mimicking physiological stimuli through controlled doses and site-specific interventions. This concept suggests that immune signaling can be selectively enhanced in target sites by integrating molecular triggers derived from parasitic organisms, mild metabolic stressors such as subtoxic ethanol, and peripheral sensory stimulation. These stimuli are expected to engage conserved neuroimmune and metabolic pathways, promoting localized activation of innate and adaptive immune components. The hypothesis remains theoretical and requires confirmation through structured in vitro and in vivo studies. Key risks include allergic sensitization, cytotoxicity, and unintended systemic immune activation. No therapeutic claims are made. The proposed concept offers a testable strategy for restoring immune function in conditions of surveillance system failure and may serve as a basis for future developments of spatially targeted immunomodulators. Introduction Deep immune suppression poses a serious challenge to restoring effective immune surveillance, particularly in the tumor microenvironment, in sepsis, and in chronic viral infections. Existing immunotherapeutic strategies, including cytokine-based interventions, have demonstrated partial efficacy in preclinical settings. For example, IL-12 administration induces IFN-γ and TNFα production, promoting Th1 polarization and CD8 + T cell activation [1]. Local delivery of IL-12 has been shown to enhance CD8 + infiltration and promote tumor microenvironment remodeling [2]. In sterile inflammatory conditions, activation of the NLRP3 inflammasome by damage-associated molecular patterns (DAMPs) initiates innate immune responses [3]. However, optimal immune activation requires coordinated interaction of both innate and adaptive components [4]. This article describes a set of hypothetical modules aimed at restoring localized immune function using physiologically relevant stimuli. These concepts are purely theoretical and require systematic testing in laboratory models. Potential risks include immunological side effects such as allergic reactions and off-target cytotoxicity. The proposed strategies are not intended for clinical use and should be limited to controlled experimental studies. The hypothesis We hypothesize that spatially confined low-dose stimuli mimicking physiological signals can initiate activation of innate immunity in states of profound immune suppression. This activation can occur without triggering systemic immune responses, thereby preserving overall immune homeostasis. The proposed mechanism involves conserved biological pathways, including pattern recognition receptors, cellular stress responses, and neuroimmune interfaces, through the action of contextspecific molecular and physical signals. These signals, originating from parasitic interactions, transient metabolic disturbances, or peripheral sensory signals, may restore local immune reactivity and facilitate interaction between innate and adaptive components. This concept remains theoretical and requires structured experimental testing. * Corresponding author. E-mail addresses: [email protected], [email protected] (M. Novruzov). Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/ymehy https://doi.org/10.1016/j.mehy.2025.111848 Received 21 October 2025; Received in revised form 9 November 2025; Accepted 6 December 2025 Medical Hypotheses 206 (2026) 111848 Available online 7 December 2025 0306-9877/© 2025 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies. Evolution of hypothesis Parasite-derived molecular triggers Controlled activation of immune surveillance via ectoparasitic triggers One proposed mechanism for localized immune reactivation involves molecular patterns derived from ectoparasitic organisms. Salivary components of Cimex lectularius have been shown to possess immunomodulatory properties, acting as adjuvants that engage innate immune sensors such as TLR2, TLR4, and NLRP3. These components also promote mast cell degranulation and neuropeptide release, collectively mimicking damage-associated molecular patterns (DAMPs) and influencing the regulation of IL-1β, TNFα , neutrophil and eosinophil recruitment, as well as nociceptor activation [5–8,9]. In conceptual experimental models, sterilized or synthetically replicated salivary peptides—such as phospholipase A2 (PLA2) or anticoagulant analogues—may be applied to ex vivo skin systems to evaluate leukocyte migration, cytokine expression profiles, and localized immune reactivity. These studies would aim to determine whether parasitederived signals can serve as spatially confined immune activators under conditions of surveillance collapse (Fig. 1). Phospholipase A2 (PLA2) from Apis mellifera Recombinant phospholipase A2 (PLA2), a key component of Apis mellifera venom, has been shown to activate mast cells and dendritic cells, leading to enhanced local inflammation, improved antigen presentation, and recruitment of innate immune effectors [10–14]. These properties indicate potential utility in restoring immune surveillance under conditions of suppression. To minimize adverse reactions, lowimmunogenic PLA2 variants should be selected, and dosing should be carefully calibrated to avoid systemic activation or cytotoxicity. Conceptually, PLA2 could serve as a local immune primer when used under controlled experimental conditions. (Fig. 2). For all PLA2 constructs and parasitic peptide-based candidates, we advise mandatory preclinical screening for allergenicity and reactivity. This screening should include IgE/IgG1 serology (both in vitro and in vivo) to find any pre-existing or induced Th2 responses. Also, carry out mast cell degranulation tests (β-hexosaminidase release, histamineELISA) on primary human mast cells or validated lines, along with basophil activation tests if possible. Any candidates showing high IgE binding or notable degranulation should be removed. Adjust engineering and formulation to lower allergenicity by choosing lowimmunogenic isoforms, designing point mutations or truncated options that eliminate dominant IgE-epitopes while keeping mechanistic activity, and formulating in liposomes or other nanoparticles to limit immediate tissue exposure and lessen direct contact with mast cells. Always include heat-inactivated or enzymatically inactive controls, dose titrations, and local delivery (either intradermally or subcutaneously) with monitoring of sentinel markers. Metabolic stress as immune trigger Subtoxic ethanol exposure Low doses of ethanol have been shown to activate innate immune signaling pathways, including TLR4, MAPK, and HSP70, in various preclinical models [15–19,20]. This response may serve as a local immune preconditioner in conditions of profound immunosuppression. Conceptually, transient metabolic stress induced by subtoxic ethanol exposure may activate monocytes and natural killer (NK) cells, modulate cytokine release patterns, and enhance local immune readiness. Experimental validation will require dose titration, reversibility testing, and assessment of spatial confinement to avoid systemic effects. (Fig. 3). Sensory-stimulated immune signaling Peripheral electrical stimulation targeting sensory fibers A and C causes the release of neuropeptides such as substance P and calcitonin gene-related peptide (CGRP), which in turn activate macrophages and mast cells [21–25]. This neuroimmune interaction may serve as a spatially limited mechanism for initiating local immune responses under conditions of suppression. Experimental modulation of stimulation parameters, including intensity and frequency, allows characterization of dose–response and evaluation of immune outcomes. Key indicators include the expression of adhesion molecules, the mobilization of Fig. 1. Visualization of the effect of Cimex lectularius. Fig. 2. Visualization of the effect of Phospholipase A2 (PLA2) from Apis mellifera. M. Novruzov et al. Medical Hypotheses 206 (2026) 111848 2 immune cells, and the production of cytokines, which together determine the degree and specificity of local immune activation (Fig 4). When describing stimulation parameters, it is important to note that sequence analysis tools, like transformer networks, are able to record time-based links between waveform aspects and immune readouts. This enables a quantitative mapping of stimulation intensity, frequency, and duty cycle to dynamic molecular and cellular responses [26]. Local Immune Activation Methods Method Exposure/trigger Immune effect Cimex lectularius Salivary proteins interact with TLR2/4 and NLRP3 Activation of innate immunity, release of cytokines Phospholipase A2 (PLA2) from Apis mellifera Phospholipase A2 activates NLRP3 and leukocytes Inflammatory response, secretion of cytokines Subtoxic ethanol exposure Low–dose ethanol activates TLR4, MAPK, HSP70 Production of IL–6, TNF– α , activation of monocytes and NK cells Peripheral electrical stimulation of A/C fibers Electrical impulses release Substance P and CGRP Activation of macrophages and mast cells, expression of adhesion molecules, cell mobilization, and cytokine release Target indications per inducer We think of molecule designs, subtoxic metabolism boosts, and peripheral sensory stimulation as separate inputs feeding into a single local neural-immune pathway. The shared goal of each piece is to start a combined activation of pattern-sensing receptors (like TLR2/4), cell stress answers (like turning on HSP70), and the NLRP3-driven sequence, plus the release of neuropeptides (Substance P, CGRP) and proinflammation cytokines (IL-1β, TNF α , IL-6). These parts make a local web of cell-to-cell actions: neuron → mast cell/macrophage → dendritic cell → monocyte/NK → endothelium, where adhesion molecules and chemokines control hiring. This map tells how different physical and molecule signals can end up in the same local activation without a system-wide flush of cytokines. This hypothesis complements existing local adjuvants and on‑tumor PRR agonists by proposing a multimodal, low‑dose approach in which parasite‑derived peptides, transient metabolic stress and peripheral sensory inputs converge on shared neuroimmune nodes. Integrative transcriptomic and network‑pharmacology readouts are proposed to distinguish targeted local reactivation from nonspecific inflammation and to reveal combinatorial synergies [27]. Parasite-derived molecules can be used to address certain conditions. Peptides from parasites and PLA2 analogs that don’t cause a strong immune response work well as initial stimulants for tumors that don’t trigger much immunity, like some pancreatic, colorectal, and prostate cancers. They can also help with long-lasting wounds, skin infections related to biofilms, and granulomas in specific areas. These sites often have issues with PRR/NLRP3 signaling, build-up of myeloid cells that suppress the immune system, problems with DC maturation, and physical barriers that stop leukocytes from entering. Delivering parasite-like PRR agonists to the area can restart innate sensing, boost interaction between mast cells and DCs, and restore antigen presentation while limiting the spread of cytokines throughout the body. Important tests include checking for allergic reactions (IgE/IgG1), testing mast cell/ basophil activation, using local dosing with sustained-release formulations, and monitoring for Type-2 skewing (ST2/IL-33) to find any unwanted polarization. Subtoxic metabolic stress can also be used to address certain conditions. Brief, localized metabolic stress, like small doses of ethanol, may be good for tissues where metabolic changes cause innate hyporesponsiveness, such as tumors with reduced metabolism (melanoma, ovarian, some lung cancers), tissue reservoirs of chronic viral infection, and areas that are tolerant to endotoxins after sepsis. These conditions involve lactate-driven suppression, hypoxia, HSP dysregulation, and epigenetic programs that lower NF-κB/AP-1 and inflammasome activation. Short, controlled metabolic disruption can engage HSP/AP-1 nodes and temporarily reverse transcriptional tolerance, allowing chemokine and inflammasome signaling to restart. Important tests include precise local PK/PD, monitoring redox and ferroptosis (GSH/GSSG, MDA, GPX4, 4-HNE), having reversibility measures in place, and antioxidant rescue plans. Stimulating peripheral sensory nerves can address certain conditions. Targeted electrical stimulation of A and C sensory fibers is suitable for barrier and surface conditions where the link between nerves and the immune system is key. Examples are long-lasting dermatitis/atopic lesions, persistent skin viral infections, mucosal niches in some IBD models, and dermal metastases with little inflammation. In these diseases, the release of neuropeptides from nociceptors is reduced, and changed adhesion molecule expression limits local leukocyte recruitment. Localized stimulation can restore Substance P/CGRP-mediated mast cell and macrophage activation, increase adhesion molecules, and recruit effector cells without causing widespread cytokine amplification. Important tests include adjusting waveform parameters, monitoring pain-related behavior, measuring TAC1/CALCA and adhesion molecules at the same time, and using transformer-based sequence analysis to map how the stimulus affects the temporal response. Limitations of the hypothesis The proposed modules are conceptual and based on preclinical observations, with limited evidence of transferability to models of profound immunosuppression. Each approach carries certain risks that must be considered when conducting controlled experiments. Inducer Proposed target indications Pathophysiologic rationale Key readouts Suggested preclinical models PLA2/ parasite–derived peptides Immune–cold solid tumours; chronic non–healing wounds; biofilm–associated infections Restore PRR/NLRP3 sensing and boost local antigen presentation; remodel suppressive myeloid niches Local IL–1β; CD8 +infiltration; DC markers; IgE/IgG1 Subcutaneous/orthotopic tumour models; biofilm wound models; ex–vivo skin explants Subtoxic ethanol (probe) Metabolically suppressed tumour niches; endotoxin–tolerant tissues; chronic viral reservoirs Transient engagement of HSP/AP–1 nodes to reverse transcriptional tolerance with limited systemic load HSP70; FOS/JUN; local IL–6/ TNF α ; GSH/GSSG; MDA Orthotopic low–metabolism tumours; chronic infection models; endotoxin–tolerance models Peripheral sensory stimulation Barrier and mucosal lesions: chronic dermatitis, dermal metastases, mucosal niches in IBD Nociceptor activation → Substance P/ CGRP release → mast cell/macrophage activation and increased adhesion/ recruitment TAC1/CALCA; adhesion molecules; local cell recruitment; pain/behavior metrics Chronic dermatitis models; mucosal infection/IBD models; dermal metastasis models Multimodal low–dose combinations Lesions refractory to single modalities; complex suppressive microenvironments Synergistic engagement of PRR, stress nodes and neuroimmune axis to produce focused reactivation Multi–omics signature (transcriptome/proteome); enhanced local clearance without systemic IL–6/CRP rise 2 ×2 factorial designs in listed models with sentinel safety cohorts M. Novruzov et al. Medical Hypotheses 206 (2026) 111848 3 Phospholipase A2 (PLA2) and related parasitic peptides may exhibit allergenic or cytotoxic effects, requiring careful dose titration and structural modification. Ethanol-based immunomodulation is highly dose-dependent; excessive exposure may paradoxically exacerbate immunosuppression. Peripheral sensory stimulation lacks cell specificity and may cause nociceptive side effects or off-target neuroimmune activation. Overall, the hypothesis requires validation across multiple experimental systems, including tumor-bearing, septic, and virally infected models. No clinical applicability is implied at this stage. Besides the general restrictions, any studies with PLA2 and peptides from parasites should have specific steps to lower the risk of allergies. This includes doing IgE/IgG1 tests beforehand, checking how mast cells break down, and, if possible, testing how basophils are activated. It is best to use versions with less allergy risk (like native low-immunogenic isoforms, point mutants, or shortened proteins) and put them in liposomal or other slow-release carriers to reduce the highest local exposure. Experiments should include carefully adjusting doses, validating each step, and having clear stop points if there are signs of overreaction (like eosinophils spreading, more histamine in plasma, symptoms of anaphylaxis, or major local necrosis). If these steps aren’t done, the candidates should not move on to in-vivo trials. In our study, ethanol is only for short-term, controlled metabolic stress induction and not a treatment suggestion. When looking at what ethanol does, remember doses, even if small, can vary depending on tissue, redox state, and if toxins or drugs were present before. Be careful of neuroimmune states where microglia aren’t as active, like in mild hypothermia [28]. These states might change how the body reacts to metabolic stress, possibly making reactivation impossible or harmful. Also, redox state and a tendency to ferroptosis could change the outcome. If there’s oxidative damage, think about protective steps, like using quercetin-type flavonoids, or stop exposures altogether. These limits mean experiments need tight controls, clear steps, and defined stopping rules. Tissue redox state and ferroptosis susceptibility may affect how cells respond to metabolic stress. If oxidative damage is high, trying to reactivate cells could cause cell death instead of recovery. Thus, redox state markers and ferroptosis indicators (MDA, GSH/GSSG, GPX4, 4HNE) should be included in basic assessments to properly understand results and guide experimental decisions. If ferroptosis is likely, consider initial tests using antioxidants like quercetin [29] to see if the outcome can be safely changed. Clinical case reports illustrate that localised or initially organrestricted immune perturbations can, in some cases, progress to lifethreatening systemic conditions. For example, reported cases of autoimmune encephalitis that developed into haemophagocytic lymphohistiocytosis demonstrate how uncontrolled central neuroimmune activation can escalate into a systemic hyperinflammatory picture. Similarly, reports of neutrophilic dermatoses (e.g., Sweet’s syndrome) following vaccination show that local immune triggers sometimes lead to systemic manifestations and require early recognition and intervention [30,31]. These clinical examples confirm the need for strict stop criteria, monitoring of systemic markers, and pre-prescribed algorithms for rapid suppression of reactions in preclinical protocols. Hypothesis testing To confirm this hypothesis, structured tests must be conducted on preclinical models characterized by immune suppression, including animals with tumors, septic models, and chronic viral infection systems. In the case of triggers derived from parasites, synthesized or sterilized peptides can be applied to specific areas of the skin to assess leukocyte migration, cytokine release, and behavioral correlates of immune activation. Modified variants of phospholipase A2 (PLA2) should be evaluated for activation thresholds, immunogenicity, and cytotoxicity using dose–response protocols. Subtoxic ethanol exposure should be titrated to determine concentrations that activate monocytes and natural killer (NK) cells without inducing systemic suppression. Cytokine analysis and reversibility tests will be important for determining safe and effective ranges. Peripheral electrical stimulation should be calibrated for intensity and frequency to determine optimal conditions for adhesion molecule expression and cytokine induction. Multidimensional readouts, including flow cytometry, cytokine panels, and behavioral tests, will be used to correlate each trigger with measurable re-engagement of the immune system. Subcutaneous administration may be explored as an alternative route of delivery for peptides derived from parasites and PLA2 Fig. 3. Visualization of the effect of ethanol. Fig. 4. Visualization of the effect of Peripheral Electrical Stimulation of A and C Fibers. M. Novruzov et al. Medical Hypotheses 206 (2026) 111848 4 constructs, allowing for control of spatial targeting and comparative analysis of local and systemic effects. In experiments with ’subtoxic ethanol,’ ethanol is viewed as a shortterm probe of metabolic stress to test the sensitivity of the local immune network, not as a treatment. The experimental process must have clearly defined exposure details (concentration, frequency, duration), monitoring of oxidative stress and cell death markers, and stop rules (see below). If signs of a systemic response or cell damage markers appear, stop the exposure and start a recovery phase with controls. Experimental designs must include comparison situations where known microglia-suppressing or immune-modulating conditions (like mild hypothermia) are used as negative controls to prove that reactivation is not a general result of the planned stimuli. Redox status tests and ferroptosis indicators should be part of the main measurement set. If ferroptosis signs are found, intervention plans (e.g., lipid peroxide antagonists or antioxidants like quercetin) and/or stopping further exposures need to be in place. Stop criteria: 1. Local increase in cytokine system markers above a predetermined threshold (e.g., plasma IL-6 >X pg/mL or CRP above the normal range for the model) — immediate cessation of exposure. 2. Significant increase in oxidative stress indicators in tissue samples (e. g., increase in MDA levels/decrease in GSH/GSSG below the threshold) — stop and initiate recovery measures. 3. Ferroptosis biomarkers (e.g., decrease in GPX4, increase in 4-HNE or specific lipid peroxidation products) — immediate stop and addition of protective intervention (quercetin or analogues) or refusal of further doses. 4. Clinical/behavioural indicators of deterioration (in animal behaviour or obvious signs of pain/distress) — stop the experiment and analyse the causes. 5. Any unjustified systemic activation (fever, significant increase in systemic cytokines) — immediate cessation and observation. To address local reactivation, we suggest identifying and measuring particular molecular markers as testable endpoints. Practically, this means using both specific stress-response markers and proinflammatory signatures (see table). It also means using available omics methods to spot unexpected or combined signals. For example, we can use automated methylomic feature extraction to assess epigenetic changes in tissues. We can also use multi-omics mapping of AP-1/stress pathways to confirm the involvement of cellular stress responses [32,33]. We anticipate that validation of local reactivation will require a consistent increase in several markers (transcription and protein) from a focal panel in the local site, without a increase in systemic markers (plasma IL-6/CRP). Another way to validate local reactivation is to find a clear difference in profile signatures between local and systemic samples using omics analysis. To ensure that the proposed inducers elicit a controlled local immune response rather than an adverse systemic reaction, all experimental protocols incorporate multi-layered safety measures. Thes include: −Preclinical allergenicity and cytotoxicity screening, including IgE/ IgG1 serology, mast cell degranulation assays, and basophil activation tests. −Spatially confined delivery, using liposomal, hydrogel, or nanoparticle formulations to restrict exposure and reduce peak tissue concentrations. −Dose titration and sentinel cohorts, with predefined stopping rules based on systemic cytokine levels (e.g., IL-6, CRP), oxidative stress markers (e.g., MDA, GSH/GSSG), and ferroptosis indicators (e.g., GPX4, 4-HNE). −Behavioral and clinical monitoring, including pain/distress scoring and temperature tracking. −Use of enzymatically inactive or heat-inactivated controls, to confirm that observed effects are stimulus-specific. −Reversibility testing, including antioxidant rescue arms (e.g., quercetin) to mitigate redox-related toxicity. −Temporal modeling of stimulus–response relationships, using transformer-based sequence analysis to optimize stimulation parameters and avoid overstimulation. These safeguards aim to validate local immune reactivation while preventing systemic spillover, allergic sensitization, or tissue damage. Suggested marker panel Implications If confirmed, the proposed strategy of local immune reactivation could have a number of important implications for immunology and therapeutic development. First, the identification of controllable physiological triggers could serve as a basis for the development of new treatments for immunosuppressive conditions. Such approaches could complement existing systemic treatments, including cytokine-based therapies (e.g., IL-12), by offering a spatially targeted alternative with lower toxicity for initiating or restoring immune activity in compromised microenvironments. Second, the hypothesis is entirely falsifiable. If experimental data consistently show that doses sufficient for local immune activation also cause systemic effects such as fever, elevated C-reactive protein or IL-6 Category Marker (gene/protein) Rationale Methods Stress response/heat shock HSPA1A (HSP70) Indicator of cellular stress response and modulator of TLR/ NLR signaling qPCR; ELISA or Western blot Inflammasome/ pro–inflammatory NLRP3; IL1B Core inflammasome sensor and effector cytokine for local innate activation qPCR; ELISA Pattern recognition receptors TLR2; TLR4 Receptors engaged by parasite–derived patterns and DAMPs qPCR; IHC Neuropeptide signaling TAC1 (Substance P); CALCA (CGRP) Markers of sensory neuron activation and neuroimmune coupling qPCR; LC–MS or targeted ELISA AP–1 transcriptional node FOS; JUN Integrator of stress and inflammatory signaling; multi–omics AP–1 readout qPCR; phospho–Western; transcriptomics Redox status GSH/GSSG; MDA Readouts of oxidative stress that modulate outcome and toxicity Biochemical assays; LC–MS Ferroptosis susceptibility GPX4; 4–HNE Markers of lipid peroxidation and ferroptotic vulnerability Western blot; ELISA; LC–MS Cellular infiltration CD68 (macrophages); MPO (neutrophils); CD3/CD8 Quantify immune cell recruitment and composition IHC/IF; image analysis Systemic spillover controls IL6; CRP Simple clinical markers to detect unwanted systemic inflammation ELISA; clinical chemistry M. Novruzov et al. Medical Hypotheses 206 (2026) 111848 5 levels, or worsen underlying suppression (as may occur with ethanol), the hypothesis will be rejected. Confirmation will require evidence of improved clearance of primary foci (e.g., tumor regression or reduction in pathogen load) following local intervention without concomitant systemic immune enhancement. Third, the hypothesis contributes to a mechanistic understanding of the peripheral neuroimmune axis. In particular, it highlights how external physical stimuli and mild stress signals can be used to modulate immune cell function in suppressive states. This understanding may be relevant for chronic inflammatory and autoimmune conditions, where precise localized immune modulation is therapeutically desirable. It’s possible that parasite molecules, metabolic stress, and sensory stimulation work together, since they all seem to affect similar pathways related to the nervous system, the immune system, and stress responses. All three seem to involve things like pattern recognition receptors (TLR2/4), stress sensors (HSP70, AP-1), and immune activation through neuropeptides (Substance P, CGRP). This leads to a signaling cascade that includes mast cells, macrophages, dendritic cells, and endothelial adhesion molecules, coordinating immune cell recruitment and activation. By using small amounts of stimuli from different areas, we hope to get a stronger and more focused immune reaction than we would from just one stimulus. More work is being planned to try different combinations and see if they have additive or synergistic on immune markers, cell infiltration, and safety. While the current hypothesis focuses on malignancy, sepsis, and chronic viral infection, the underlying principle of spatially confined immune reactivation may be extrapolated to other pathologies characterized by localized immune suppression. These include chronic wounds, biofilm-associated infections, granulomatous diseases, and certain neurodegenerative conditions with impaired microglial priming. Extrapolation is justified when the target pathology exhibits (1) focal failure of innate immune sensing, (2) poor recruitment or activation of effector cells, and (3) a microenvironment permissive to localized intervention without systemic spillover. However, each new application must undergo independent validation, including tissue-specific safety profiling, biomarker mapping, and confirmation of spatial confinement. The proposed framework is modular and adaptable, but not universally applicable without disease-specific testing. Previous studies have demonstrated measurable progress in enhancing immune responses across the pathologies targeted in this hypothesis. In cancer and chronic viral infections, researchers have identified stem-like T cells capable of sustaining long-term immune responses despite exhaustion, offering a basis for durable reactivation strategies [34]. In sepsis and malignancy, overlapping immunosuppressive mechanisms such as myeloid dysfunction and PRR desensitization have been targeted using cytokine-based therapies and inflammasome modulators. Additionally, vaccine-based approaches and immunotherapies have shown promise in virus-associated cancers, highlighting the feasibility of restoring immune surveillance through controlled stimulation [35]. These findings support the plausibility of spatially confined immune reactivation and justify further preclinical testing of multimodal inducers. Conclusions This hypothesis describes three distinct and controllable physiological entry points—molecular patterns originating from parasites, mild metabolic stress, and peripheral sensory stimulation—as potential mechanisms for local reactivation of immunity under conditions of deep suppression. The basic premise is that innate immune signaling can be spatially restricted and selectively engaged without causing systemic toxicity. Although this concept remains theoretical, it provides a structured framework for experimental investigation. Careful testing in relevant preclinical models is needed to determine the feasibility, safety, and immunological impact of these modules as components of a novel immunomodulatory strategy. Ethics statement This manuscript presents hypotheses and does not report experimental work. No ethical approval required. Future research would seek appropriate approvals. Disclaimer Research concept for discussion and preclinical testing only. This document contains no clinical instructions and is not medical advice. Consent statement/ethical approval This work does not require ethical approval as there are no procedures in human or animal subjects. Funding support This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. AI-assisted statement No generative artificial intelligence was used at any point duringthe writing or preparation of this manuscript. CRediT authorship contribution statement Murad Novruzov: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Project administration, Methodology, Investigation, Conceptualization. Marziyya Mammadova: Writing – review & editing, Writing – original draft, Validation, Methodology. Waseem Ullah Khan: Writing – review & editing, Writing – original draft, Validation, Methodology, Data curation. Ulkar Shiraliyeva: Writing – original draft, Methodology, Formal analysis, Data curation. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] Nastala CL, Edington HD, McKinney TG, Tahara H, Nalesnik MA, Brunda MJ, Gately MK, Wolf SF, Schreiber RD, Storkus WJ, et al. Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production. J Immunol 1994;153(4):1697–706. PMID: 7913943. https://pubmed. ncbi.nlm.nih.gov/7913943/. [2] Colombo Mario P, Giorgio Trinchieri A, Mario B, Colombo P, Trinchieri Giorgio, et al. Interleukin-12 in anti-tumor immunity and immunotherapy. Crit Rev Immunol. 2002. https://doi.org/10.1016/S1359-6101(01)00032-6. [3] Li J, Li L, He J, Xu J, Bao F. The NLRP3 inflammasome is a potential mechanism and therapeutic target for perioperative neurocognitive disorders. Front Aging Neurosci 2023;14:1072003. https://doi.org/10.3389/fnagi.2022.1072003. [4] Wang R, Lan C, Benlagha K, Camara NOS, Miller H, Kubo M, et al. The interaction of innate immune and adaptive immune system. MedComm 2024;5(10):e714. [5] Meraj S, Salcedo-Porras N, Lowenberger C, Gries G. Activation of immune pathways in common bed bugs, Cimex lectularius, in response to bacterial immune challenges - a transcriptomics analysis. Front Immunol 2024;15:1384193. https:// doi.org/10.3389/fimmu.2024.1384193. [6] Rodrigues Moreira Guerra L, et al. Bedbug salivation patterns during hematophagy in the skin of a mammalian host. J Insect Physiol 2021;131:1235. https://doi.org/ 10.1016/j.jinsphys.2021.104235. [7] Meraj S, Gries G. The innate and adaptive immune system of the common bed bug, cimex lectularius: current knowledge and research opportunities. IntechOpen; 2022. Hemiptera - Recent Updates [Working Title]. Available from: 10.5772/ intechopen.107383. [8] Francischetti IM, Calvo E, Andersen JF, Pham VM, Favreau AJ, Barbian KD, et al. Insight into the sialome of the bed bug, cimex lectularius. J Proteome Res 2010;9 (8):3820–31. https://doi.org/10.1021/pr1000169. M. Novruzov et al. Medical Hypotheses 206 (2026) 111848 6 [9] Hajduˇ sek O, Síma R, Ayll´ on N, Jaloveck´ a M, Perner J, de la Fuente J, et al. Interaction of the tick immune system with transmitted pathogens. Front Cell Infect Microbiol 2013;3:26. https://doi.org/10.3389/fcimb.2013.00026. [10] Palm NW, Rosenstein RK, Yu S, Schenten DD, Florsheim E, Medzhitov R. Bee venom phospholipase A2 induces a primary type 2 response that is dependent on the receptor ST2 and confers protective immunity. Immunity 2013;39(5):976–85. https://doi.org/10.1016/j.immuni.2013.10.006. [11] Muntean M, Florea A. Phospholipase A2-a significant bio-active molecule in honeybee (Apis mellifera L.) venom. Molecules 2025;30(12):2623. https://doi. org/10.3390/molecules30122623. Published 2025 Jun 17. [12] Cui Z, Zhou Z, Sun Z, Duan J, Liu R, Qi C, et al. Melittin and phospholipase A2: Promising anti-cancer candidates from bee venom. Biomed Pharmacother = Biomedecine & pharmacotherapie 2024;179:117385. https://doi.org/10.1016/j. biopha.2024.117385. [13] Müller U, Akdis CA, Fricker M, Akdis M, Blesken T, Bettens F, et al. Successful immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces specific T-cell anergy in patients allergic to bee venom. J Allergy Clin Immunol 1998;101(6 Pt 1):747–54. https://doi.org/10.1016/S0091-6749(98) 70402-6. [14] Ye M, Chung HS, Lee C, Hyun Song J, Shim I, Kim YS, et al. Bee venom phospholipase A2 ameliorates motor dysfunction and modulates microglia activation in Parkinson’s disease alpha-synuclein transgenic mice. Exp Mol Med 2016;48(7):e244. [15] Muralidharan S, Ambade A, Fulham MA, Deshpande J, Catalano D, Mandrekar P. Moderate alcohol induces stress proteins HSF1 and hsp70 and inhibits proinflammatory cytokines resulting in endotoxin tolerance. J Immunol (Baltimore, Md. : 1950) 2014;193(4):1975–87. https://doi.org/10.4049/ jimmunol.1303468. [16] Mandrekar P, Catalano D, Jeliazkova V, Kodys K. Alcohol exposure regulates heat shock transcription factor binding and heat shock proteins 70 and 90 in monocytes and macrophages: implication for TNF-alpha regulation. J Leukoc Biol 2008;84(5): 1335–45. https://doi.org/10.1189/jlb.0407256. [17] Hulina-Tomaˇ skovi´ c A, Somborac-Baˇ cura A, Grdi´ c Rajkovi´ c M, Bosnar M, Samarˇ zija M, Rumora L. Effects of extracellular Hsp70 and cigarette smoke on differentiated THP-1 cells and human monocyte-derived macrophages. Mol Immunol 2019;111:53–63. https://doi.org/10.1016/j.molimm.2019.04.002. [18] Zhang B, Qi R. The dual-function of HSP70 in immune response and tumor immunity: from molecular regulation to therapeutic innovations. Front Immunol 2025;16:1587414. https://doi.org/10.3389/fimmu.2025.1587414. [19] Afrazi A, Sodhi CP, Good M, Jia H, Siggers R, Yazji I, Ma C, Neal MD, Prindle T, Grant ZS, Branca MF, Ozolek J, Chang EB, Hackam DJ. Intracellular heat shock protein-70 negatively regulates TLR4 signaling in the newborn intestinal epithelium. J. Immunol. (Baltimore, Md. : 1950) 2012;188(9):4543–57. https:// doi.org/10.4049/jimmunol.1103114. [20] Hulina A, Grdi´ c Rajkovi´ c M, Jakˇ si´ c Despot D, Jeli´ c D, Dojder A, ˇ Cepelak I, et al. Extracellular Hsp70 induces inflammation and modulates LPS/LTA-stimulated inflammatory response in THP-1 cells. Cell Stress Chaperones 2018;23(3):373–84. https://doi.org/10.1007/s12192-017-0847-0. [21] Kulalert W, Wells AC, Link VM, Lim AI, Bouladoux N, Nagai M, et al. The neuroimmune CGRP-RAMP1 axis tunes cutaneous adaptive immunity to the microbiota. PNAS 2024;121(11):e2322574121. https://doi.org/10.1073/ pnas.2322574121. [22] Klein Wolterink RGJ, Wu GS, Chiu IM, Veiga-Fernandes H. Neuroimmune interactions in peripheral organs. Annu Rev Neurosci 2022;45:339–60. https://doi. org/10.1146/annurev-neuro-111020-105359. [23] Fan Y, Kim DH, Ryu Y, Chang S, Lee BH, Yang CH, et al. Neuropeptides SP and CGRP underlie the electrical properties of acupoints. Front Neurosci 2018;12:907. https://doi.org/10.3389/fnins.2018.00907. [24] Wang Z, Song K, Kim BS, Manion J. Sensory neuroimmune interactions at the barrier. Mucosal Immunol 2024;17(6):1151–60. https://doi.org/10.1016/j. mucimm.2024.10.001. [25] Gupta S, Viotti A, Eichwald T, Roger A, Kaufmann E, Othman R, et al. Navigating the blurred path of mixed neuroimmune signaling. J Allergy Clin Immunol 2024; 153(4):924–38. https://doi.org/10.1016/j.jaci.2024.02.006. [26] Shi S, Liu W. B2-ViT net: broad vision transformer network with broad attention for seizure prediction. IEEE Trans Neural Syst Rehabil Eng 2024;32:178–88. https:// doi.org/10.1109/TNSRE.2023.3346955/. [27] Cheng M, Li T, Hu E, et al. A novel strategy of integrating network pharmacology and transcriptome reveals antiapoptotic mechanisms of Buyang Huanwu Decoction in treating intracerebral hemorrhage. J Ethnopharmacol 2024;319(Pt 1):117123. https://doi.org/10.1016/j.jep.2023.117123. [28] Ma WX, Wang SW, Fan QW, et al. Mild hypothermia reduces lipopolysaccharideinduced microglial activation via down-regulation of Tent5c. Biochem Biophys Res Commun 2024;706:149767. https://doi.org/10.1016/j.bbrc.2024.149767. [29] Cheng X, Huang J, Li H, Quercetin, et al. A promising therapy for diabetic encephalopathy through inhibition of hippocampal ferroptosis. Phytomedicine 2024;126:154887. https://doi.org/10.1016/j.phymed.2023.154887. [30] Huang L, Tan J, Lin P, Chen Z, Huang Q, Yao H, et al. Autoimmune encephalitis followed by hemophagocytic lymph histiocytosis: a case report. Front Immunol 2024;15:1383255. https://doi.org/10.3389/fimmu.2024.1383255. [31] Jia Y, Fu B, Dong L, Zhao M. Sweet syndrome induced by SARS-CoV-2 vaccines: a systematic review of patient-report studies. Hum Vaccin Immunother 2023;19(2): 2217076. https://doi.org/10.1080/21645515.2023.2217076. [32] Feng X, Xin R, Wu J, Zheng J, Wang C, Yu C. AutoFE-Pointer: Auto-weighted feature extractor based on pointer network for DNA methylation prediction. Int J Biol Macromol 2025;311(Pt 4):143668. https://doi.org/10.1016/j. ijbiomac.2025.143668. [33] Li F, Tian J, Zhang L, He H, Song D. A multi-omics approach to reveal critical mechanisms of activator protein 1 (AP-1). Biomed Pharmacother =Biomedecine & pharmacotherapie 2024;178:117225. https://doi.org/10.1016/j. biopha.2024.117225. [34] Tripathi AK, Srivastava Y. The overlapping biology of sepsis and cancer and therapeutic implications. Biomedicines 2025;13(6):1280. https://doi.org/ 10.3390/biomedicines13061280. [35] Isaguliants MG, Trotsenko I, Buonaguro FM. An overview of “chronic viral infection and cancer, openings for vaccines” virtual symposium of the TechVac network - december 16-17, 2021. Infectious Agent Cancer 2022;17(Suppl 2):28. https://doi.org/10.1186/s13027-022-00436-0. M. Novruzov et al. Medical Hypotheses 206 (2026) 111848 7