This review presents a systematic synthesis of the principal tumor immunotherapy strategies and their corresponding resistance mechanisms. Immunotherapies—including antibody-based therapies, adoptive cell therapies, immune modulators, and novel approaches such as oncolytic viruses and cancer vaccines—work by stimulating or enhancing the patient's immune system to target cancer cells. Nevertheless, they commonly encounter resistance in clinical applications. Resistance mechanisms predominantly stem from tumor-intrinsic factors and tumor microenvironment (TME) factors. To surmount resistance, combination therapies and personalized treatment strategies grounded in TME profiling and biomarkers represent critical future directions.

Breast cancer brain metastasis (BCBM) is driven by microenvironmental remodeling across three interconnected phases: the primary tumor microenvironment (TME) licenses dissemination, the pre-metastatic niche (PMN) primes the brain, and the established metastatic niche sustains outgrowth through central nervous system (CNS)-resident cell interactions. These phases are individually established; we integrate them through cross-phase signaling axes, exemplified by the proposed IL-6$\rightarrow$extracellular vesicle (EV)$\rightarrow$blood-brain barrier (BBB) disruption cascade, that link tumor-associated macrophage-driven epithelial-mesenchymal transition to PMN conditioning and niche maintenance. We integrate single-cell and spatial transcriptomic insights, discuss brain-specific mechanisms including astrocytic STAT3/connexin 43 signaling, neuronal contributions, and the neurovascular unit, and evaluate emerging therapies with emphasis on antibody-drug conjugates with intracranial activity. Subtype-specific differences between HER2-positive and triple-negative breast cancer brain metastases and key translational barriers are systematically addressed.