Editorial: Exploring Immunomodulation to Balance Maladaptive Inflammation and Restore Tissue Homeostasis

David M SMADJA^1*Maxime Jeljeli²Alexandre G. Lellouch^1,2

• ¹Hematology, INSERM U970 Paris Centre de Recherche Cardiovasculaire (PARCC), Paris, France
• ²Cedars-Sinai Cancer, Los Angeles, United States

The COVID-19 pandemic reignited global interest in how immune responses can oscillate between hyperinflammation and profound suppression. Severe SARS-CoV-2 infections, marked by thromboinflammatory cascades and immune dysregulation, exemplify the importance of immunomodulation in maintaining tissue homeostasis. The pandemic also opened the way for renewed appreciation of the immune system's dual role-not only as a defender against pathogens but also as a regulator of repair, resolution, and tolerance. This Research Topic brings together original research and reviews that collectively explore how immunomodulatory interventions may rebalance inflammation, restore tissue integrity, and prevent immune exhaustion or immune escape. The articles span acute infections such as sepsis and COVID-19, to chronic inflammatory states and tumor immunology, while integrating systemic and local perspectives on immune control. Two contributions address the complexity of immune dynamics in sepsis. In a prospective study of critically ill patients, Samuelsen et al. examined the trajectories of immunoparalysis biomarkers-including mHLA-DR expression, lymphocyte counts, and cytokine responsesover the first 14 days of illness (Samuelsen et al.). They observed diverging recovery patterns between septic and non-septic patients and revealed that ex vivo cytokine stimulation may outperform classical markers in predicting immune recovery. Importantly, while mHLA-DR increased more in non-septic patients, absolute lymphocyte counts and TNF-α production showed more rapid recovery in those with sepsis, suggesting distinct temporal windows for immuno-adjuvant therapy. inhibition. The study highlights an underappreciated risk: corticosteroid therapies, while immunosuppressive, may still permit potent innate activation, posing a threat for patients exposed to fungal pathogens. The work also suggests that NLRP3 inhibitors might play a protective role in such contexts, though risks of dampening host defense must be carefully evaluated. Extending the lessons of COVID-19 to the systems level, Murad et al. employed a computational modeling framework to investigate how SARS-CoV-2 infection perturbs the immunogenic tumors. The authors advocate for integrating heating with immunotherapies to stimulate innate and adaptive responses synergistically. Across these six contributions, a unifying insight becomes clear: the immune system cannot be simplistically classified as pro-or anti-inflammatory. Rather, its behavior is highly contextdependent, governed by a dynamic interplay of temporal factors, tissue-specific microenvironments, and therapeutic interventions. This complexity becomes especially evident in the diverse immunological landscapes of acute infections, metabolic disorders, malignancies, and systemic inflammatory conditions. Particularly, conditions such as chronic inflammation and vascular dysfunction exemplify how persistent immune dysregulation can lead to pathological remodeling and tissue damage. Similarly, hyperthermia, in an infectious context or induced therapeutically, has demonstrated profound immunomodulatory effects including enhanced antigen presentation, improved immune cell trafficking, and reshaped cytokine responses. These examples highlight the nuanced roles that stressors play in either perpetuating immune imbalance or facilitating its resolution. Collectively, these studies underscore a paradigm shift in immunotherapy, from blunt immune suppression toward precise, adaptive modulation of immune pathways. The goal is not only to dampen inflammation, but to recalibrate the immune response so that it is both effective in eliminating threats and restrained enough to avoid collateral tissue damage. By elucidating the molecular and cellular mechanisms underlying immune imbalance, and showcasing innovative approaches to restoring homeostasis, this research topic highlights the growing promise of context-aware, precision immunotherapies. These insights lay the groundwork for developing interventions that are tailored not only to disease type, but also to its specific immunological and physiological context, paving the way for the next generation of personalized medicine.