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Despite the documented role of host immune heterogeneity and bacterial genotypic background in determining infection outcomes, their interplay remains largely uncharacterized. We investigated the\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      (MTB)-human macrophage interaction, considering both macrophage phenotypic variability and MTB genetic diversity. Using single-cell techniques, we show how diverse MTB lineages fine-tune phagosome acidification differently based on macrophage phenotype (M1, M2), revealing very heterogeneous host-pathogen interactions. Our findings underscore the multiplicity of outcomes due to the combinatorial interplay between MTB lineages and macrophage phenotypes, which may have implications for the proper design of host-directed therapies.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        The intricate interplay among host, pathogen, and environmental factors significantly contributes to susceptibility and clinical presentation of tuberculosis. These multifaceted mechanisms are often overlooked in tuberculosis studies, hindering our comprehensive understanding of infection progression and impeding the development of effective host-directed therapies, which offer benefits such as reduced drug resistance emergence and heightened host compatibility. Contrary to the prevailing hypothesis, the results observed in this study demonstrate the nuanced response of different\n                        <jats:italic toggle=\"yes\">M. tuberculosis<\/jats:italic>\n                        lineages within distinct macrophage phenotypes in terms of phagosome acidification. The findings of our investigation delineate a crucial yet under-characterized aspect of tuberculosis pathogenesis, emphasizing how the interactions between different\n                        <jats:italic toggle=\"yes\">M. tuberculosis<\/jats:italic>\n                        lineages and macrophage phenotypes could significantly influence the efficacy of host-directed therapies, particularly those targeting phagolysosomal maturation. More broadly, recognizing the impact of both\n                        <jats:italic toggle=\"yes\">M. tuberculosis<\/jats:italic>\n                        and macrophage heterogeneity is paramount in the development of effective strategies to combat tuberculosis.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.03762-25","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:01:28Z","timestamp":1784552488000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["<i>Mycobacterium tuberculosis<\/i>\n                    diversity and macrophage heterogeneity dictate phagosomal acidification"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3386-377X","authenticated-orcid":false,"given":"Matteo","family":"Chiacchiaretta","sequence":"first","affiliation":[{"name":"Emerging Bacterial Pathogens Unit, IRCCS San Raffaele Scientific Institute","place":["Milano, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9674-0959","authenticated-orcid":false,"given":"Rita","family":"Sorrentino","sequence":"additional","affiliation":[{"name":"Emerging Bacterial Pathogens Unit, IRCCS San Raffaele Scientific Institute","place":["Milano, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Bresciani","sequence":"additional","affiliation":[{"name":"Emerging Bacterial Pathogens Unit, IRCCS San Raffaele Scientific Institute","place":["Milano, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2681-9383","authenticated-orcid":false,"given":"Alessandra","family":"Aiello","sequence":"additional","affiliation":[{"name":"Translational Research Unit, National Institute for Infectious Diseases-IRCCS L. 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