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In cancers, an acidic tumor microenvironment (TME; extracellular pH\n                    <jats:sub>e<\/jats:sub>\n                    \u2009~\u20096.4\u20136.8) imposes a biophysical and metabolic stress that could destabilize this interface. Experimental studies indicate that even modest acidification could significantly reduce integrin\u2010dependent adhesion strength, delay actin clearance at the synapse, and suppress store\u2010operated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    entry, thereby leading to marked decreases in cytokine production and cytotoxic granule release. In parallel, tumor cells often maintain relative intracellular alkalinity by enhancing proton export via transporters such as NHE1, MCT1\/4, and CAIX, thereby reinforcing cortical actin \u201cshielding,\u201d metabolic resilience, and resistance to perforin\u2010mediated killing. These asymmetric pH adaptations may therefore establish a hidden checkpoint at the IS that favors tumor survival. We synthesize current evidence on pH\u2010dependent regulation of actin dynamics, integrin activation, mitochondrial function, and Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channels (Orai1\/STIM1); highlight key methodological gaps, including the lack of approaches combining real\u2010time intra\u2010 and extracellular pH and Ca\n                    <jats:sup>2+<\/jats:sup>\n                    imaging; and discuss enabling technologies such as microfluidic platforms, genetically encoded pH sensors, and multiparametric single\u2010cell assays. Finally, we outline therapeutic strategies aimed at modulating pH (buffers, inhibitors of NHE1, MCTs, V\u2010ATPases, or CAIX) or engineering pH\u2010resistant effector cells and consider how these approaches could synergize with immune checkpoint blockade, CAR\u2010T cells, and bispecific antibodies. Viewing acidosis as a druggable checkpoint reframes the IS as a bidirectional, pH\u2010tuned system and suggests testable paths to restore antitumor immunity.\n                  <\/jats:p>","DOI":"10.1155\/jimr\/5768926","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T20:50:43Z","timestamp":1777495843000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Hidden Checkpoint: Bidirectional pH Remodeling of the Immunological Synapse in Cancer, Methods, and Therapeutic 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