From immune desert to hot tumor: the tripartite synergy of tumor microenvironment-exosomes-immunogenic cell death in pioneering solutions

The global incidence of cancer remains persistently high, with associated mortality rates remaining elevated owing to the challenges of early diagnosis and propensity for metastasis. The immunosuppressive "cold tumor" within the tumor microenvironment (TME), characterized by hypoxia, metabolic abnormalities, and immunosuppressive cellular infiltration, represents a key factor in treatment resistance and the failure of immunotherapies. Existing therapeutic approaches exhibit significant limitations that hinder curative outcomes. Tumor-derived exosomes (TEXs) frequently carry pro-cancer biomolecules, rendering single-exosome targeting strategies insufficient to reverse TME-mediated immunosuppression. Concurrently, danger signaling molecules released during immunogenic cell death (ICD) are readily neutralized by the immunosuppressive TME, resulting in inadequate and transient anti-tumor immune responses. Recent studies indicate that the TME, exosomes, and ICD do not function as isolated entities but rather constitute an interlinked signaling network. The TME modulates exosome biogenesis and release through hypoxic and inflammatory microenvironments while simultaneously attenuating the effects of ICD, thereby promoting immune evasion. Exosomes play a dual role in intercellular communication: TEXs amplify immunosuppressive signals, whereas engineered exosomes can deliver ICD inducers or immunomodulatory factors to reshape the immune state of the TME. ICD attempts to reverse TME suppression by releasing damage-associated molecular patterns (DAMPs); however, its effects require exosome-mediated long-range signal amplification and matrix penetration. Co-targeting the TME-exosome-ICD axis provides a mechanistic framework for enhancing the immunotherapy response by boosting DAMPs presentation, promoting antigen release, and facilitating immune cell infiltration. This approach also establishes a novel paradigm for reversing immunologically "cold" tumors towards an immunologically activated phenotype.