# Advances in intratumoral immunotherapy from a neuro-immune-endocrine perspective for breast cancer treatment

## TL;DR

This paper reviews how intratumoral immunotherapy, considering the neuro-immune-endocrine interactions, can improve breast cancer treatment by targeting the tumor and its surrounding environment.

## Contribution

The paper introduces a novel perspective on intratumoral immunotherapy by integrating the neuro-immune-endocrine network to better understand and treat breast cancer.

## Key findings

- Intratumoral delivery of therapies can reduce systemic toxicity and improve treatment outcomes.
- The tumor microenvironment (TME) plays a dynamic role in shaping tumor behavior and response to treatment.
- Neurotransmitters, hormones, and immune cells interact within the TME to influence tumor progression and treatment efficacy.

## Abstract

The incidence rate of breast cancer continues to grow worldwide and is increasingly occurring in younger women. Although treatments have improved, they present several distinct challenges, as life-threatening side effects, relapse, metastasis, and ultimately death in women and men of productive ages. The immunotherapeutic strategies are focused on the postoperative context, and the systemic intravenous therapies have shown benefits in some patient populations with overall survivor rates higher in hormone-dependent breast cancer, but still high relapse rates, especially in more aggressive cancers such as HER2+ and triple negative. To halt tumor progression, it is necessary to identify all players involved, but most importantly, acknowledge the interactions of tumor cells with their surroundings. 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. By elucidating these interactions, we aim to 1) predict treatment outcomes, 2) explain why some patients do not respond to innovative therapies, and 3) propose novel strategies for modifying the TME through targeted delivery of therapeutic agents with new materials. Furthermore, this approach paves the way for tumor-targeted modulation of other potential endocrine modulators, cytokine/chemokine delivery, and neurotransmitter modulation within the TME, representing a novel frontier in cancer treatment.