Cancer Stem Cells Decide the Fate of Cancer Immunotherapy by Remodeling Tumor Microenvironment

Sep 24, 2025Cancer control : journal of the Moffitt Cancer Center

Cancer Stem Cells May Influence Cancer Immunotherapy by Changing the Tumor Environment

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Abstract

(CSCs) may drive immune evasion and therapy resistance in the (TME).

CSCs influence the TME by secreting factors that suppress the immune response and by recruiting regulatory immune cells.
The TME can protect CSCs through conditions like low oxygen, altered cell metabolism, and the presence of immune-suppressive cells.
This interplay between CSCs and the TME may contribute to tumor progression and resistance to immunotherapy.
CSCs can evade detection by the immune system and resist cell death induced by therapies.
Targeting CSCs while modifying the TME could potentially improve the effectiveness of immunotherapies.

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Success of cancer immunotherapy (CIT) is intricately influenced by the (TME), a complex ecosystem that encompasses immune cells, stromal elements, and extracellular components. Despite the clinical breakthroughs of immune-checkpoint inhibitors (ICIs), adoptive cell therapies, cancer vaccines, and other immunotherapeutic interventions, many patients fail to respond and eventually die. Emerging evidence points to (CSCs) as critical drivers of immune evasion, therapy-resistance, and tumor relapse. CSCs modulate the TME by secreting immune-suppressive factors, recruiting regulatory immune cells, and inducing phenotype-switching of anti-tumor TME subsets, thereby creating a protective niche that hinders immune surveillance. Conversely, the TME protects CSCs through hypoxia, altered metabolism, and immuno-suppressive cell populations. This bi-directional crosstalk supports tumor progression and provides resistance to immunotherapeutic strategies mainly by: (i) escaping immune-recognition and inhibiting active T cellshigh immune-checkpoint molecule expression, (ii) creating immunosuppressive pro-tumor environment, and (iii) evading immune-mediated apoptosis of CSCs along with therapy-induced enrichment of their pool. Targeting CSCs in concert with reprogramming the TMECSC-directed agents, metabolic modulators, or combinatorial immunotherapies, therefore, offers a promising avenue to overcome immunotherapy-resistance and achieve durable clinical responses. This review discusses the deeper mechanistic understanding of CSC-TME interactions, in light of designing next-generation immunotherapies with broader efficacy across diverse tumor types. via via

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Cancer Stem Cells Decide the Fate of Cancer Immunotherapy by Remodeling Tumor Microenvironment

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