Innovative approaches in the treatment of hematologic malignancies: the role of CRISPR-engineered microbiomes along the gut-immune axis in immunotherapy development

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Hematologic malignancies encompass a diverse group of disorders characterized by the abnormal proliferation of blood-forming cells within the bone marrow, lymphatic system, and peripheral blood. These include leukemia, lymphoma, multiple myeloma, and other related conditions, which collectively pose significant health challenges worldwide. Despite advances in diagnosis and treatment, these malignancies often exhibit complex pathophysiology, heterogeneity, and resistance to conventional therapies, necessitating ongoing research to develop more effective and targeted interventions. Originally discovered as an adaptive immune mechanism in bacteria, CRISPR-Cas systems have been adapted for targeted gene editing in human cells. This technology offers unprecedented opportunities to correct genetic mutations, modulate gene expression, and engineer biological systems, including microbiomes. To address these challenges, we review recent strategies that harness CRISPR-engineered gut commensals as precision “living therapeutics” to modulate host immunity and directly target malignant clones. In this review, a living therapeutic is used operationally to mean a nonpathogenic live microorganism engineered with at least one therapeutic module and one control module, for example, a disease-responsive sensing circuit, a payload-production or secretion function, and basic biocontainment or stability safeguards. We organize our discussion around three mechanisms: (i) microbial secretion of immunomodulators (e.g., IL‑15, IFN‑γ, PD‑1/PD‑L1 blockers); (ii) delivery of tumor‑lytic payloads via phage‑ or nanoparticle‑mediated CRISPR systems; and (iii) production of anticancer metabolites (e.g., butyrate, indole derivatives). Preclinical models demonstrate that these engineered strains can reduce tumor burden by > 60%, restore CAR‑T cell function, and overcome drug resistance. We also analyze key technical barriers, strain stability, biocontainment, off‑target effects, and propose solutions including auxotrophic kill switches and AI‑guided strain optimization. Finally, we outline future directions, from in situ phage delivery to multi‑omics–driven patient stratification. CRISPR-microbiome editing represents a promising strategy for hematologic oncology, particularly because blood cancers arise in bone marrow and secondary lymphoid niches rather than in a compact solid mass. Although microbiome–immunotherapy interactions are also important in solid tumors, the strongest translational evidence currently available is concentrated in solid-tumor ICI response studies and in hematologic settings such as CAR-T and HSCT; therefore, this review is intentionally scoped to blood cancers. CRISPR-engineered bacteria can be programmed to colonize the gut or TME and secrete immunomodulators, amplifying anti-tumor immunity while minimizing systemic toxicity. Using CRISPR-edited bacteria, can design strains that express and secrete nanobodies or small-molecule antagonists targeting PD-1 or PD-L1. Phages and nanoparticles serve as CRISPR vehicles to edit tumor genomes in situ, inducing lytic payloads like apoptosis inducers or DNA breaks in oncogenes Nanoparticles carrying CRISPR payloads can be engineered for activation upon encountering specific microbial metabolites or environmental cues only present near the tumor. Emerging non-viral delivery platforms, including targeted lipid nanoparticles and other programmable carriers, may eventually enable in vivo programming of T cells to express CARs and reduce dependence on ex vivo manufacturing; however, this remains preclinical and requires further validation.

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