Chapter 6 │ Page 210 adaptive immunity will be key to ensure an optimal integration into cancer immunotherapy. However, sometimes it is necessary to first take a step back and gain insights into the basic mechanisms underlying NTP's cellular e ects, as these can provide a stronger foundation for understanding its broader impact on complex biological processes such as immunological signaling and therapeutic response. In that regard, NTP is postulated to exert its anti-tumor e ects through three intertwined modes of action: i) direct e ects on exposed tumor, ii) bystander e ects on neighboring cells that are not directly exposed, and iii) abscopal e ects mediated through systemic immune triggering. Intercellular communication, particularly through GJs (GJIC), may play a central role in all three of these e ects. Our literature review (chapter 5) highlighted that GJs are highly sensitive to oxidative stress and the main e ector species in NTP can stimulate channel opening. Thus, GJs may amplify direct cytotoxic e ects of NTP by enabling the intercellular spread of ROS and oxidative damage. For bystander e ects, links can be made with the radiotherapy field, where it is well established that damaging signals can be transferred from irradiated to non-irradiated neighboring cells via GJIC. A similar mechanism may also underlie NTP-induced bystander responses, allowing stress signals to propagate through the tumor tissue and beyond the treatment area. This would provide a plausible explanation for the biological responses observed far beyond the physical penetration depth of the reactive species. Finally, in the context of systemic immune responses, GJs may also contribute to the abscopal e ects of NTP by influencing immune cell communication. Specifically, the formation of a stable immunological synapse, which is critical for e ective immune-immune or immune–target cell interaction, is known to involve functional GJs. As such, NTPinduced changes to GJ expression or function could impact immune synapse formation and downstream immune activation. Altogether, gap junctions emerge as
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