MRSA remains a major cause of severe community‑ and hospital‑acquired infections, and rising antibiotic resistance underscores the need for new therapeutic strategies. Beyond their classical role in hemostasis, platelets are increasingly recognized as sentinels of host defense, responsible for sensing pathogens and releasing antimicrobial factors. iPSC‑PLTs—produced ex vivo from human iPS cells—offer distinct advantages because they can be engineered by genome editing to fine‑tune immune functions, manufactured at scale with consistent quality, and developed and banked as "off‑the‑shelf" products, particularly with HLA class I-deficient designs. The researchers thus examined whether iPSC‑PLTs possess intrinsic antibacterial activity against MRSA and sought to define the mechanisms that govern this response.

In side‑by‑side assays with donor‑derived peripheral blood platelets, three independent iPSC‑PLT clones showed robust bactericidal activity comparable to that of peripheral blood platelets. These results establish iPSC‑PLTs as active participants in antibacterial defense rather than passive hemostatic bystanders. Although classical platelet activation markers rose only modestly upon exposure to MRSA, pharmacologic inhibition of key platelet pathways—including integrin, COX‑1, P2Y1, and P2Y12 signaling—significantly reduced bacterial killing. This apparent paradox—low‑grade activation yet high functional impact—suggests that subtle shifts in integrin activation and granule biology can translate into meaningful antimicrobial effects.

Next, the research team investigated how physiological context may shape the antibacterial response. While human plasma alone accelerated MRSA growth, its presence in platelet-bacteria co‑cultures consistently enhanced iPSC‑PLT-mediated killing, indicating that host factors in plasma help tip the balance toward defense. The study pinpointed a mechanism behind this enhancement: engagement of FcγRIIA—the platelet receptor for IgG—proved crucial, as pretreatment with an FcγRIIA‑blocking antibody curtailed bactericidal activity both with and without plasma, implicating IgG as an amplifier of bacteria‑induced platelet responses.

As for the innate immune sensing system, the TLR2-MyD88 axis emerged as a necessary trigger. iPSC‑PLTs expressed TLR2 and responded to canonical TLR2 ligands, such as peptidoglycan and Pam3CSK4, with calcium mobilization and increased activation marker expression. When the researchers used CRISPR/Cas9 to knock out MYD88 —the key adaptor downstream of TLR2—the resulting iPSC‑PLTs displayed diminished activation and a significant loss of MRSA‑killing capacity, directly linking TLR2-MyD88 signaling to platelet antibacterial function.

Notably, bacteria possess countermeasures. The research team found that MRSA's pore‑forming α‑toxin suppressed platelet antimicrobial activity, as an isogenic α‑toxin-deficient strain—despite slightly faster growth kinetics—was consistently more susceptible to killing by iPSC‑PLTs than its wild‑type counterpart, thereby indicating that this toxin blunts platelet defenses without broadly elevating conventional activation readouts.

Together, these findings outline a coherent framework: iPSC‑PLTs detect Gram‑positive pathogen cues through TLR2, signal via MyD88 to achieve a primed activation state, and cooperate with humoral immunity through IgG-FcγRIIA interactions to neutralize MRSA, while bacterial α‑toxin functions to dampen this response. Beyond these mechanistic insights, the work highlights the translational promise of iPSC‑PLTs as an off‑the‑shelf, gene‑editable cell product. Because they can be manufactured at scale and engineered to modify immune pathways—or even rendered HLA‑independent—iPSC‑PLTs offer a tractable platform to interrogate platelet immunity and to design next‑generation adjunctive treatments that complement antibiotics against escalating antimicrobial resistance.

• doi: 10.1016/j.rpth.2026.103374