Dissecting the TMEM132A-EGFR Dependency to Unlock Translational Therapeutic Opportunities for Pan-Solid Tumor

Abstract

Solid tumors remain refractory to conventional treatments, yet cell surface proteins, by virtue of their extracellular accessibility and critical roles in tumor signaling, represent an attractive class of targets for precision-targeted therapy. Here, we report that TMEM132A is an essential and previously unrecognized pan-cancer target. TMEM132A interacts directly with EGFR and stabilizes its expression, thereby tethering EGFR at the plasma membrane and sustaining constitutive activation of lipid synthesis. Mechanistically, the TMEM132A-EGFR axis promotes lipogenesis by facilitating SREBP nuclear translocation, which in turn upregulates ACLY and ACSS2 expression to drive acetyl-CoA production and downstream lipid biosynthesis, ultimately disrupting lipid droplet homeostasis. To therapeutically target this axis, we developed a nanobody, LFNanoT132A#3, which effectively blocks the TMEM132A-EGFR interaction, abrogates downstream signaling activation, and potently inhibits proliferation across multiple solid tumor types. Notably, LFNanoT132A also exerts robust antitumor activity against H1975 xenografts, a model resistant to first- and second- generation EGFR inhibitors, underscoring its potential to overcome conventional drug resistance. Our findings establish TMEM132A#3 as a critical node in membrane-tethered oncogenic signaling and metabolic rewiring, and position LFNanoT132A#3 as a promising therapeutic candidate for precision cancer therapy.

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BibTeX RIS

BibTeX

@misc{liu2026dissecting,
  title = {{Dissecting the TMEM132A-EGFR Dependency to Unlock Translational Therapeutic Opportunities for Pan-Solid Tumor}},
  author = {X. Liu and Y. Fu and Q. Ni and C. Ning and J. Wang and M. Wu and C. Zhang and J. Wang and J. Qian and W. Fang and D. Zhang and X. Li and F. Zhao and L. Gong and J. Yao and N. Song and Y. He and X. Wei and C. Qin and J. Wang},
  howpublished = {bioRxiv},
  year = {2026},
  month = aug,
  doi = {10.64898/2026.08.30.746586},
  url = {https://www.biorxiv.org/content/10.64898/2026.08.30.746586v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Dissecting the TMEM132A-EGFR Dependency to Unlock Translational Therapeutic Opportunities for Pan-Solid Tumor
AU  - X. Liu
AU  - Y. Fu
AU  - Q. Ni
AU  - C. Ning
AU  - J. Wang
AU  - M. Wu
AU  - C. Zhang
AU  - J. Wang
AU  - J. Qian
AU  - W. Fang
AU  - D. Zhang
AU  - X. Li
AU  - F. Zhao
AU  - L. Gong
AU  - J. Yao
AU  - N. Song
AU  - Y. He
AU  - X. Wei
AU  - C. Qin
AU  - J. Wang
PY  - 2026
DA  - 2026/08/30
PB  - bioRxiv
DO  - 10.64898/2026.08.30.746586
UR  - https://www.biorxiv.org/content/10.64898/2026.08.30.746586v1
AB  - Solid tumors remain refractory to conventional treatments, yet cell surface proteins, by virtue of their extracellular accessibility and critical roles in tumor signaling, represent an attractive class of targets for precision-targeted therapy. Here, we report that TMEM132A is an essential and previously unrecognized pan-cancer target. TMEM132A interacts directly with EGFR and stabilizes its expression, thereby tethering EGFR at the plasma membrane and sustaining constitutive activation of lipid synthesis. Mechanistically, the TMEM132A-EGFR axis promotes lipogenesis by facilitating SREBP nuclear translocation, which in turn upregulates ACLY and ACSS2 expression to drive acetyl-CoA production and downstream lipid biosynthesis, ultimately disrupting lipid droplet homeostasis. To therapeutically target this axis, we developed a nanobody, LFNanoT132A#3, which effectively blocks the TMEM132A-EGFR interaction, abrogates downstream signaling activation, and potently inhibits proliferation across multiple solid tumor types. Notably, LFNanoT132A also exerts robust antitumor activity against H1975 xenografts, a model resistant to first- and second- generation EGFR inhibitors, underscoring its potential to overcome conventional drug resistance. Our findings establish TMEM132A#3 as a critical node in membrane-tethered oncogenic signaling and metabolic rewiring, and position LFNanoT132A#3 as a promising therapeutic candidate for precision cancer therapy.
ER  -

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