Clinical bottom line
Tissue-resident memory T cells (TRM) have emerged as key players in the pathogenesis and persistence of various autoimmune diseases by maintaining localized immune memory and driving chronic inflammation. Emerging therapies targeting TRM—through metabolic modulation, depletion, or functional inhibition—offer a promising avenue for durable remission in autoimmune conditions refractory to conventional immunosuppression. However, clinical evidence remains preliminary, and safety profiles require careful evaluation given TRM’s role in protective immunity. Clinicians should consider TRM-targeted approaches as investigational and weigh potential benefits against risks of impaired tissue immune surveillance.
What the evidence shows
TRM cells are a distinct subset of memory T cells that permanently reside in non-lymphoid tissues, including skin, kidney, and mucosa, where they provide rapid local immune responses (Ginsberg et al., 2023). In autoimmune diseases such as lupus nephritis and other renal autoimmune conditions, TRM cells accumulate in affected tissues and contribute to ongoing inflammation and tissue damage (Hellmig et al., 2026; Ginsberg et al., 2023). Their persistence despite systemic immunosuppression suggests they may underlie disease relapses and resistance to therapy.
Recent mechanistic studies have identified metabolic pathways critical for TRM survival and function, such as lipid metabolism and mitochondrial fitness, which can be therapeutically targeted. For example, Waris Hussain Nawaz et al. (2026) demonstrated that metabolic starvation of perifollicular TRM cells in alopecia areata models reduced pathogenic T cell persistence and promoted durable remission, highlighting a novel therapeutic strategy.
Tabatabaei et al. (2026) reviewed evolving therapeutic approaches targeting CD8+ TRM cells across autoimmune and immune-mediated inflammatory diseases, emphasizing strategies including selective depletion, blockade of retention signals (e.g., CD69, CD103), and modulation of cytokine milieus that sustain TRM. These approaches are in early-phase clinical development or preclinical stages but show promise in reducing tissue-specific autoimmunity.
Municio et al. (2021) further contextualize TRM targeting within the broader concept of modulating trained immunity and tissue immune memory, underscoring the potential for durable disease control by erasing pathogenic immune memory at the tissue level.
Caveats and uncertainty
Despite promising preclinical data, robust clinical trial evidence on TRM-targeted therapies in autoimmune diseases is lacking. The heterogeneity of TRM subsets across tissues and diseases complicates the identification of universal targets. Moreover, TRM cells contribute to protective immunity against infections and tumors; thus, their depletion or functional inhibition may increase infection risk or impair tumor surveillance (Ginsberg et al., 2023).
Safety data from analogous immune cell-targeted therapies, such as B cell depletion, highlight the need for vigilance regarding immunosuppression-related adverse events (Bruce et al., 2013). The balance between therapeutic efficacy and preservation of beneficial tissue immunity remains a critical unknown.
Additionally, biomarkers to identify pathogenic TRM populations and monitor therapeutic response are not yet standardized, limiting patient selection and treatment optimization.
How this may change practice
If validated in clinical trials, TRM-targeted therapies could represent a paradigm shift in managing refractory autoimmune diseases by addressing tissue-resident pathogenic immune memory that conventional systemic therapies fail to eradicate. This may enable more durable remission, reduce relapse rates, and potentially allow tapering of broad immunosuppression.
Clinicians should stay informed about emerging clinical data and consider enrolling eligible patients in trials exploring TRM-targeted interventions. Integration of tissue immunophenotyping and metabolic profiling may become important for personalized therapy selection.
Until more evidence accrues, TRM-targeted approaches remain experimental. Their use outside clinical trials should be cautious, with careful monitoring for infectious complications and immune dysregulation.