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Mycobacterium tuberculosis (Mtb) survives within macrophages by evading host antimicrobial mechanisms, including phagosome maturation. In a clonal population of macrophages sorted by endocytic capacity, we have shown that cell cycle progression correlates with endocytic trafficking. With fluorescent Mtb reporter strains, we show that this host-intrinsic variation shapes the redox and pH environment of intracellular Mtb, consistent with the emerging concept that heterogeneity in host cell physiology — even under unperturbed conditions — determines intracellular Mtb fitness. Moreover, Mtb is not merely a passive passenger but utilizes its surface lipids to actively arrest the host cell cycle, locking the host macrophage in a state that favors bacterial survival. Using bulk RNA sequencing of sorted endocytic subpopulations, we are mapping the transcriptional landscape of these distinct macrophage states to identify the host factors underlying cell-to-cell heterogeneity, and investigating how the resulting stress heterogeneity influences differential drug tolerance in Mtb. Together, this study aims to uncover the dynamic interplay between host cell heterogeneity and bacterial adaptation to reveal new strategies for overcoming Mtb drug tolerance.