Advances in Intratumoral Immunotherapy and from a Neuro-Immune-Endocrine Modulation Perspective for Breast Cancer Treatment

Claudia Angelica Garay-CanalesMariana Segovia-MendozaYair Rodríguez SantiagoKaren Elizabeth Nava-CastroMaría RíosValeria VargasDiana Lizeth Ruiz-AntonioCésar Antonio Zavala-LópezCarmen Gómez De LeónJorge Morales-Montor^*

• National Autonomous University of Mexico, México City, Mexico

The tumor microenvironment (TME) has emerged as a conceptual framework that underscores the collective influence of cellular, structural, and signaling elements coexisting around the tumor. These components do not merely act as passive bystanders; rather, they form a dynamic milieu that shapes tumor behavior, therapeutic responsiveness, and disease trajectory. This reinforces the notion that effective interventions must address not only malignant cells but also the broader contextual landscape in which they evolve. While intratumor refers to heterogeneity within a single tumor, the TME encompasses the surrounding non-cancerous cells, molecules, and vasculature that interact with the tumor, collectively forming a dynamic landscape that modulates therapeutic responses and disease trajectory. The neuro-immune-endocrine (NIE) network plays a complex role in breast cancer, with the nervous system influencing tumor growth, immune evasion, and metastasis through neurotransmitters and neuropeptides. The endocrine system influences the TME through hormones such as estrogens, even in non-estrogen-dependent tumors in breast cancer. At the same time, immune cells interact with both neural and endocrine components, responding through cytokine release and phenotype modulation, thereby mounting a permissive or cytotoxic response to combat tumors. Stress, which activates the sympathetic nervous system, can affect immune cells and hormone release, impacting treatment adherence and positive prognosis. Nowadays, local intratumoral delivery with diverse mechanisms of action has been shown to mitigate systemic toxic effects and ensure targeted delivery, and has progressed to clinical trials, demonstrating promising outcomes. These mechanisms include, but are not limited to, triggering immune responses using pathogens, enhancing immune responses with recombinant cytokines, inhibiting immune checkpoints with monoclonal antibodies, or combining two or more of these strategies. Despite the high mortality associated with breast cancer in aggressive subtypes and its characterization by well-defined primary lesions, the clinical application of non-systemic intratumoral chemotherapy remains limited. In this review, we summarize effective intratumoral immunotherapeutic approaches for inhibiting tumor growth and/or metastasis in breast cancer. Specifically, we focus on the interactions within the NIE network that contribute to a sustained resolution of breast cancer.