Overcoming immune resistance through tumor microenvironment reprogramming: Emerging immunotherapeutic strategies and...

Breast, ovarian, cervical, and endometrial malignancies remain major causes of cancer-related morbidity and mortality due to metastatic progression, immune evasion, and the limited durability of therapeutic responses. Although immune checkpoint inhibitors have improved outcomes in selected patients, their efficacy is frequently constrained by profoundly immunosuppressive tumor microenvironments (TMEs). This review summarizes the molecular mechanisms driving immune resistance across these malignancies and highlights emerging strategies to improve immunotherapeutic efficacy. The roles of classical and emerging immune checkpoints, including Programmed cell death receptor 1 (PD-1), Programmed cell death-ligand 1 (PD-L1), T-cell immunoglobulin and mucin domain 3 (TIM-3), Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), Lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), V-domain Ig suppressor of T-cell activation (VISTA), and Siglec-mediated glyco-checkpoints, are discussed in the context of T-cell dysfunction and tumor immune escape. Mechanisms regulating immune cell infiltration, including chemokine signaling, stromal remodeling, and cytokine networks, are also examined for their contributions to immune exclusion or activation within the TME. Furthermore, metabolic reprogramming pathways, including lactate accumulation, adenosine signaling, and tryptophan catabolism, are evaluated for their roles in suppressing antitumor immunity and promoting tumor progression. The therapeutic potential of epigenetic modulation to restore antigen presentation, interferon signaling, and immune responsiveness is also highlighted. Finally, advances in antibody-drug conjugates, cancer vaccines, and adoptive cellular therapies are discussed as promising strategies that combine targeted cytotoxicity with immune activation. Overall, these insights support biomarker-driven combination therapies to overcome immune resistance and improve durable clinical outcomes in breast and gynaecological malignancies.