Despite major advances in T cell-directed cancer immunotherapy, many patients fail to achieve durable responses, underscoring the need for approaches that mobilize additional arms of the immune system. The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) pathway has emerged as a central cytosolic DNA sensor that initiates robust type I interferon signaling and bridges innate and adaptive antitumor immunity. Clinically, heightened cGAS–STING activity correlates with improved survival and enhanced responsiveness to immune checkpoint blockade in subset of tumor types. Preclinical studies have further demonstrated that the pharmacologic or genetic activation of cGAS–STING suppresses tumor growth, promotes dendritic cell maturation, increases effector immune infiltration, and synergizes with PD-1/PD-L1 inhibition. However, the spectrum of tumors that derive the greatest therapeutic benefit from STING activation and the mechanisms underlying pathway silencing or non-responsiveness remain incompletely defined. In this review, we integrate mechanistic, preclinical, and clinical evidence across solid tumors and hematologic malignancies to delineate the roles of cGAS–STING as both a prognostic biomarker and a therapeutic target. Our synthesis highlights the context-dependent nature of cGAS–STING signaling, with therapeutic outcomes shaped by STING pathway integrity, tumor mutational burden, cytosolic DNA load, and the immunologic composition of the tumor microenvironment. Importantly, we examine emerging evidence that excessive, systemic, or chronic STING activation can drive immune exhaustion, tolerogenic myeloid reprogramming, and treatment-limiting toxicity, which are factors likely to contribute to efficacy limitations of the first-generation STING agonists. We further discuss how rational combination strategies, optimized delivery platforms, and the kinetic control of STING activation may overcome these barriers. Collectively, this synthesis provides a conceptual framework to guide the development of next-generation immunotherapies that leverage cGAS–STING signaling while avoiding the immunosuppressive consequences of dysregulated innate immune activation.

Viral infection is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (Allo-HSCT), largely due to its impact on and interaction with immune reconstitution. Both innate and adaptive immunity are essential for effective viral control, yet their recovery post-transplant is often delayed or functionally impaired. Emerging evidence suggests genetic variation, particularly polymorphisms in the IL28B gene (encoding IFN-λ3), as a critical factor influencing the quality and timing of immune responses during the early post-transplant period. This review explores the role of IL28B polymorphisms in shaping antiviral immunity, in general, as well as after Allo-HSCT. IL28B variants have been implicated in modulating interferon-stimulated gene (ISG) expression, natural killer (NK) cell activity, and type I/III interferon signaling, all central components of innate immune defense against viral infections. Furthermore, IL28B polymorphisms, particularly rs12979860, have been shown in both general populations and limited HSCT cohorts to alter T cell response and interferon production, affecting reactivation and clearance of multiple viruses such as cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), COVID-19, and BK polyomavirus (BKPyV) as well as Graft vs. Host disease, thereby affecting adaptive immune reconstitution and long-term viral control. Understanding how IL28B genotype alters immune dynamics in transplant recipients could enhance risk stratification for CMV and other diseases and inform personalized prophylactic or therapeutic strategies. Therefore, this review highlights IL28B as a promising biomarker and potential immunoregulatory target in the management of viral infection post-Allo-HSCT.

Advanced endometrial cancer (aEC) presents a formidable therapeutic challenge, particularly in patients with recurrent or metastatic disease. Historically, platinum-based chemotherapy is the mainstay treatment for aEC. However, the treatment paradigm has shifted with the emergence of immune checkpoint inhibitors (ICIs) and targeted therapies. Lenvatinib combined with pembrolizumab (LVB + PMB) has emerged as a promising regimen, particularly for patients with proficient mismatch repair (pMMR) tumors who typically respond poorly to ICI monotherapy. This review synthesizes recent data comparing LVB + PMB to chemotherapy, focusing on efficacy, safety, and molecular subtype-guided treatment selection. Findings from the KEYNOTE-775 and LEAP-001 trials are highlighted. We also delve into the molecular and immunologic landscape of aEC, providing a mechanistic rationale for treatment response and resistance. While LVB + PMB shows superior progression-free survival in second-line settings, its first-line application in unselected populations remains inconclusive. Therefore, strategic patient stratification and biomarker development remain key to maximizing clinical outcomes. Furthermore, we discuss the clinical implications of these findings, explore future research directions, including novel combinations and biomarkers, and provide recommendations for the evolving therapeutic landscape.

CD24 is an emerging innate immune checkpoint that regulates inflammatory and antiviral immune responses through interactions with Siglec family receptors. Although CD24 has been extensively studied in immune regulation and has recently gained attention as a therapeutic target in infectious and inflammatory diseases, its role in cancer remains incompletely understood. CD24 is overexpressed in multiple human malignancies, where accumulating evidence suggests that it promotes tumor progression and immune evasion through activation of diverse intracellular and extracellular signaling pathways. However, the importance of its subcellular localization and associated signaling remains poorly defined. Here, we investigated CD24 expression, localization, signaling associations, immune-cell infiltration, and clinical outcomes using publicly available cancer datasets, focusing on breast cancer (BRCA), cervical squamous cell carcinoma (CESC), and glioblastoma multiforme (GBM). Our analyses revealed prominent membrane-associated CD24 localization in BRCA and CESC, whereas CD24 was predominantly cytoplasmic in GBM. BRCA and CESC exhibited increased integrin β1 expression and distinct associations between CD24 and components of integrin β1/SRC and TGFβ-associated signaling networks, including MEK1 and SMAD7. In addition, we identified a structurally consistent and energetically favorable predicted interface between CD24 and Siglec-10, suggesting a mechanism by which CD24 may suppress anti-tumor immunity. Elevated CD24 expression was associated with immune-infiltration patterns consistent with an immunosuppressive tumor microenvironment in BRCA and CESC, including negative associations with M1 macrophage, CD8⁺ T-cell, and NK-cell infiltration. Importantly, high CD24 expression was associated with unfavorable overall survival in BRCA and CESC, whereas the opposite relationship was observed in GBM. Collectively, these findings suggest that the subcellular distribution of CD24 may be associated with distinct tumor signaling, the immune microenvironment, and prognostic profiles, highlighting the potential importance of CD24 localization in determining its tumor-type-specific biological functions.