Personalized cancer vaccines (PCVs) use patient-specific tumor mutations to generate immune responses against neoantigens. Clinical studies in melanoma, pancreatic cancer, lung cancer, and other settings show that individualized vaccines can induce broad and durable neoantigen-specific T-cell responses, while recent randomized data support their use in combination with immune checkpoint blockade. Nevertheless, immunogenicity does not necessarily translate into durable tumor control. A major determinant is the tumor microenvironment (TME), where myeloid, stromal, vascular, metabolic, and extracellular-matrix programs can prevent vaccine-induced lymphocytes from reaching or functioning within tumor tissue. Tumor-associated macrophages (TAMs) are particularly important because they are abundant, plastic, spatially organized, and responsive to tumor-derived cytokines, hypoxia, lipids, metabolites, and signals from cancer-associated fibroblasts and lymphocytes. This review summarizes evidence linking TAM biology to the major steps required for successful personalized vaccination, including antigen presentation, T-cell recruitment, persistence, cytotoxicity, and resistance to inhibitory signaling. Rather than treating TAMs as a uniform M2 population, we emphasize transcriptionally and spatially distinct states, including TREM2+, SPP1+, CD163+/MRC1+, PD-L1+, and CD73+ macrophages. Mechanistically, TAMs can suppress immunity through PD-L1/PD-1 signaling, IL-10, TGF-β, arginine depletion, adenosine, lipid handling, lactate-associated metabolic adaptation, extracellular-matrix remodeling, and altered chemokine gradients. We then examine therapeutic approaches involving CSF1/CSF1R, PI3Kγ, TREM2, CD73/adenosine, innate immune agonism, and macrophage reprogramming. Importantly, direct clinical evidence proving that a defined TAM subset causes failure of personalized neoantigen vaccination remains limited. Therefore, TAM-mediated vaccine resistance should currently be regarded as a biologically plausible and testable mechanism supported by convergent evidence, rather than as an established clinical biomarker. Integrating tumor genomics with single-cell, spatial, and functional immune profiling may enable biomarker-guided combinations of personalized vaccination, TAM modulation, and checkpoint blockade.