Phenotypic and targeted drug discovery in immune therapeutics: challenges, opportunities, and future directions

Nelson García Vázquez, Hossam Nada, Saurabh Upadhyay and Moustafa T. Gabr

RSC Adv., 2025, 15, 29937
DOI: 10.1039/D5RA03914B

Research Progress on Protein S-Palmitoylation in T-Cell Signaling Transduction

心忱戴

BP, 2023, 13, 115
DOI: 10.12677/BP.2023.132016

Crosstalk between protein lipidation and ubiquitination in tumor biology

Jiahong Liao, Qian Huang, Zhuoyuan Yang, Mi Zou, Junlin Ren, Ruiying Fang, Jianbin Wen, Yuan Gao, Jie Peng and Liang Hao

Apoptosis, 2026, 31
DOI: 10.1007/s10495-026-02277-3

Palmitic acid and palmitoylation in cancer: Understanding, insights, and challenges

Peipei Song, Qiwei Jiang, Xueji Wu, Lang Bu, Wei Xie, Wenyi Wei, Xiaofang Xing and Jianping Guo

The Innovation, 2025, 6, 100918
DOI: 10.1016/j.xinn.2025.100918

Membrane protein trafficking in the anti-tumor immune response: work of endosomal-lysosomal system

Yan Jin, Zhifeng Deng and Ting Zhu

Cancer Cell Int, 2022, 22
DOI: 10.1186/s12935-022-02805-6

Palmitoylation modulates antitumor immunity

Feng Tang, Jia-Long Xu, Qing Zhang, Xi Chen, Ze-Fen Wang, Ya-Di Xu and Zhi-Qiang Li

Mol Biol Rep, 2025, 52
DOI: 10.1007/s11033-025-11084-z

Research progress on S-palmitoylation modification mediated by the ZDHHC family in glioblastoma

Beiyan Tang, Wei Kang, Qiang Dong, Zhenwei Qin, Lei Duan, Xianjun Zhao, Guoqiang Yuan and Yawen Pan

Front. Cell Dev. Biol., 2024, 12
DOI: 10.3389/fcell.2024.1413708

Inhibitors of DHHC family proteins

Tong Lan, Clémence Delalande and Bryan C. Dickinson

Current Opinion in Chemical Biology, 2021, 65, 118
DOI: 10.1016/j.cbpa.2021.07.002

An HIV-1 CRISPR-Cas9 membrane trafficking screen reveals a role for PICALM intersecting endolysosomes and immunity

Paola Guizar, Ana Luiza Abdalla, Anne Monette, Kristin Davis, Ramon Edwin Caballero, Meijuan Niu, Xinyun Liu, Oluwaseun Ajibola, Thomas T. Murooka, Chen Liang and Andrew J. Mouland

iScience, 2024, 27, 110131
DOI: 10.1016/j.isci.2024.110131

PD-1 regulation in immune homeostasis and immunotherapy

Minling Gao, Jie Shi, Xiangling Xiao, Yingmeng Yao, Xu Chen, Bin Wang and Jinfang Zhang

Cancer Letters, 2024, 588, 216726
DOI: 10.1016/j.canlet.2024.216726

Processes and therapeutic perspectives of acylation modifications of lysine and cysteine in tumors

Jialin Jiang, Jiabin Chen, Shuhang Huang, Yue Tian, Lanyu Liu, Jiahui Yao, Yuzhu Zhang, Can Jiang, Xingting Zhang, Na Han, Guang Shu, Gang Yin, Li Xian Yip, Kuoran Xing, David Tai Leong and Maonan Wang

Cell Commun Signal, 2026, 24
DOI: 10.1186/s12964-026-02707-4

Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways

Rong Wang, Shiwei He, Jun Long, Yian Wang, Xianjie Jiang, Mingfen Chen and Jie Wang

Exp Hematol Oncol, 2024, 13
DOI: 10.1186/s40164-024-00515-5

Strategies for developing PD-1 inhibitors and future directions

Wensheng Chen, Yuan Huang, Wenting Pan, Meng Xu and Liang Chen

Biochemical Pharmacology, 2022, 202, 115113
DOI: 10.1016/j.bcp.2022.115113

Bridging metabolic reprogramming and targeted therapy: the critical role of S-palmitoylation in cancer

Yan Sun, Weiqiang Tang, Ye Xia, Min Xia, Gaohua Liu, Wenjie Zhang, Yajun Chen and Jing Zhong

Front. Cell Dev. Biol., 2026, 14
DOI: 10.3389/fcell.2026.1802109

Post-translational Modification of PD-1: Potential Targets for Cancer Immunotherapy

Te-An Lee, En-Yun Tsai, Shou-Hou Liu, Shih-Duo Hsu Hung, Shing-Jyh Chang, Chi-Hong Chao, Yun-Ju Lai, Hirohito Yamaguchi and Chia-Wei Li

Cancer Research, 2024, 84, 800
DOI: 10.1158/0008-5472.CAN-23-2664

Targeting ZDHHC9 potentiates anti-programmed death-ligand 1 immunotherapy of pancreatic cancer by modifying the tumor microenvironment

Zhiqing Lin, Keke Huang, Hui Guo, Manli Jia, Qiuqin Sun, Xuhao Chen, Jianmin Wu, Qingqing Yao, Peng Zhang, Sergii Vakal, Zhengzhi Zou, Haiyao Gao, Lei Ci, Jiangfan Chen and Wei Guo

Biomedicine & Pharmacotherapy, 2023, 161, 114567
DOI: 10.1016/j.biopha.2023.114567

d-mannose targets PD-1 to lysosomal degradation and enhances T cell-mediated anti-tumor immunity

Wenjing Dong, Mingen Lin, Ruonan Zhang, Xue Sun, Hongchen Li, Tianshu Liu, Yanping Xu and Lei Lv

Cancer Letters, 2024, 591, 216883
DOI: 10.1016/j.canlet.2024.216883

Protein cysteine palmitoylation in immunity and inflammation

Hening Lin

The FEBS Journal, 2021, 288, 7043
DOI: 10.1111/febs.15728

Protein palmitoylation and immune regulation in pancreatic ductal adenocarcinoma: Integrating insights from cross-cancer studies

Xiaotong Cui, Changlei Li, Xue Zhong, Ao Sun, Yingying Lan and Zusen Wang

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2026, 1881, 189532
DOI: 10.1016/j.bbcan.2026.189532

Protein S-Palmitoylation as Potential Therapeutic Target for Dermatoses

Yanhai Feng, Jianxin Wu, Hui Tang, Shunying Liu, Honglin Jia, Yi Liang, Zhenglin Li, Lingbo Li, Lingfei Li and Xia Lei

Biomolecules, 2025, 16, 53
DOI: 10.3390/biom16010053

ZDHHC12 Palmitoylates HDAC8 to Promote the Progression of Hepatocellular Carcinoma Associated with a Diet High in Saturated Fatty Acids

Xin Jin, Yulong Hong, Yongqi Zhao, Wensheng Shi, Ruilin Liu, Xinyu You, Chong Yang and Yu Zhang

Advanced Science, 2025, 12
DOI: 10.1002/advs.202505702

Diverse Roles of Protein Palmitoylation in Cancer Progression, Immunity, Stemness, and Beyond

Mingli Li, Leisi Zhang and Chun-Wei Chen

Cells, 2023, 12, 2209
DOI: 10.3390/cells12182209

Exploring Protein S-Palmitoylation: Mechanisms, Detection, and Strategies for Inhibitor Discovery

Shaojun Pei and Hai-long Piao

ACS Chem. Biol., 2024, 19, 1868
DOI: 10.1021/acschembio.4c00110

The shadow of cancer therapeutic resistance: Unveiling the role of S-palmitoylation

Xue Yang, Mengke Xu, Zhiqin Deng and Bo Xu

Drug Resistance Updates, 2025, 82, 101264
DOI: 10.1016/j.drup.2025.101264

The oxidative stress 3-like protein GsOS3L, substrate of GsSnRK1, enhances salt and cadmium stresses in soybean roots

Xiaohuan Sun, Haidong Bu, Haoran Lu, Junfeng Zhang, Qiang Li, Jialei Xiao, Xiaodong Ding and Lei Cao

Plant Science, 2025, 355, 112483
DOI: 10.1016/j.plantsci.2025.112483

Palmitoylation in cancer: decoding its roles in signal transduction, tumor immunity, and emerging therapeutic opportunities

Qiguang Lu, Jiasheng Wu, Xiaoyan Yu, Juanjuan Qian and Zhengwei Song

Front. Immunol., 2025, 16
DOI: 10.3389/fimmu.2025.1640016

The palmitoylation of gasdermin D directs its membrane translocation and pore formation during pyroptosis

Arumugam Balasubramanian, Alan Y. Hsu, Laxman Ghimire, Muhammad Tahir, Pascal Devant, Pietro Fontana, Gang Du, Xing Liu, Dang Fabin, Hiroto Kambara, Xuemei Xie, Fei Liu, Tomoya Hasegawa, Rong Xu, Hongbo Yu, Mei Chen, Steven Kolakowski, Sunia Trauger, Martin Røssel Larsen, Wenyi Wei, Hao Wu, Jonathan C. Kagan, Judy Lieberman and Hongbo R. Luo

Sci. Immunol., 2024, 9
DOI: 10.1126/sciimmunol.adn1452

Metabolic Regulation of T Cell Exhaustion

Hao Wu, Miriam Campillo Prados and Martin Vaeth

Immune Discovery, 2025, 1, 10005
DOI: 10.70322/immune.2025.10005

Protein lipidation in the tumor microenvironment: enzymology, signaling pathways, and therapeutics

Mengke Xu and Bo Xu

Mol Cancer, 2025, 24
DOI: 10.1186/s12943-025-02309-7

Post-translational modifications of immune checkpoints: molecular mechanisms, tumor microenvironment remodeling, and therapeutic implications

Hung-Chia Hsieh, Lun-Ling Ling and Yi-Ching Wang

J Biomed Sci, 2026, 33
DOI: 10.1186/s12929-025-01202-1

Control of mitochondria-associated endoplasmic reticulum membranes by protein S-palmitoylation: Novel therapeutic targets for neurodegenerative diseases

Qiangqiang He, Meiyu Qu, Tingyu Shen, Jiakun Su, Yana Xu, Chengyun Xu, Muhammad Qasim Barkat, Jibao Cai, Haibin Zhu, Ling-Hui Zeng and Ximei Wu

Ageing Research Reviews, 2023, 87, 101920
DOI: 10.1016/j.arr.2023.101920

Protein palmitoylation: A potential therapeutic target in cardiovascular diseases

Sijia Zhao, Yanyan Yang, Hong Li, Pin Sun, Xiangqin He, Chao Wang, Jingjing Zhang, Yu Tian, Tao Yu and Zhirong Jiang

Acta Pharmaceutica Sinica B, 2025, 15, 5127
DOI: 10.1016/j.apsb.2025.07.041

Targeting PD-1 post-translational modifications for improving cancer immunotherapy

Jie Shi, Chuan He, Li Chen, Xixin Xing, Wenyi Wei and Jinfang Zhang

Cell Insight, 2025, 4, 100248
DOI: 10.1016/j.cellin.2025.100248

Targeting palmitoylation: A novel frontier in cancer biology and immunotherapy

Ye Yang, Enqi Zhang, Xuanli Mao, Guohong Liu and Yunbao Pan

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2026, 1881, 189509
DOI: 10.1016/j.bbcan.2025.189509

Post-translational modifications at the crossroads of cancer metabolism and immune regulation: therapeutic opportunities and challenges

Jiahua Liu, Jiaao Sun, Chengming Li, Xiu Shan, Feng Yue and Guangzhen Wu

International Journal of Surgery, 2026, 112, 1580
DOI: 10.1097/JS9.0000000000003381

S‐palmitoylation regulates innate immune signaling pathways: molecular mechanisms and targeted therapies

Jing Cai, Jun Cui and Liqiu Wang

Eur J Immunol, 2023, 53
DOI: 10.1002/eji.202350476

Protein S-palmitoylation modification: implications in tumor and tumor immune microenvironment

Yijiao Chen, Yongsheng Li and Lei Wu

Front. Immunol., 2024, 15
DOI: 10.3389/fimmu.2024.1337478

Palmitoylation of TIM-3 promotes immune exhaustion and restrains antitumor immunity

Zhaoying Zhang, Caiyue Ren, Rong Xiao, Shuaiya Ma, Huimin Liu, Yutong Dou, Yuchen Fan, Shuo Wang, Peng Zhan, Chengjiang Gao, Xuetian Yue, Chunyang Li, Lifen Gao, Xiaohong Liang, Zhuanchang Wu and Chunhong Ma

Sci. Immunol., 2024, 9
DOI: 10.1126/sciimmunol.adp7302

ZDHHC2 promoted antimycobacterial responses by selective autophagic degradation of B-RAF and C-RAF in macrophages

Junli Sheng, Xiaolong You, Dingnai Nie, Yuling Fu, Qiao Ling, Xiaodan Yang, Yitian Chen, Li Ma and Shengfeng Hu

Sci. Adv., 2025, 11
DOI: 10.1126/sciadv.adq7706

Deubiquitinase USP24 activated by IL-6/STAT3 enhances PD-1 protein stability and suppresses T cell antitumor response

Hung-Chia Hsieh, Ming-Jer Young, Kuan-Yu Chen, Wu-Chou Su, Chien-Chung Lin, Yi-Ting Yen, Jan-Jong Hung and Yi-Ching Wang

Sci. Adv., 2025, 11
DOI: 10.1126/sciadv.adt4258

Anti-Tumor Potential of Post-Translational Modifications of PD-1

Xiaoming Xi and Wuli Zhao

CIMB, 2024, 46, 2119
DOI: 10.3390/cimb46030136

Activation and lineage specific Lag3 expression dynamics in T cells

Chaimae Khaled, Sohee Kim, Dongkyun Kim and Booki Min

The Journal of Immunology, 2026, 215
DOI: 10.1093/jimmun/vkag039

A Not-So-Ancient Grease History: Click Chemistry and Protein Lipid Modifications

Kiall F. Suazo, Keun-Young Park and Mark D. Distefano

Chem. Rev., 2021, 121, 7178
DOI: 10.1021/acs.chemrev.0c01108

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

Xiaohui Ren, Lijuan Wang, Likun Liu and Juan Liu

Front. Immunol., 2024, 15
DOI: 10.3389/fimmu.2024.1392546

Targeting LYPLAL1-mediated cGAS depalmitoylation enhances the response to anti-tumor immunotherapy

Yizeng Fan, Yang Gao, Li Nie, Tao Hou, Weichao Dan, Zixi Wang, Tianjie Liu, Yi Wei, Yuzhao Wang, Bo Liu, Taotao Que, Yuzeshi Lei, Jin Zeng, Jian Ma, Wenyi Wei and Lei Li

Molecular Cell, 2023, 83, 3520
DOI: 10.1016/j.molcel.2023.09.007

S-palmitoylation: A novel player in cancer and its emerging therapeutic implications

Ruiheng Wang, Aojia Zhuang, Yifan Wu, Jie Shen, Yanan Zhang, Peipei Liu, Anas Rabata, Nedumaran Pavithra, Shaopeng Yu, Jiangling Peng, Yaxun Huang and Duoyao Cao

Cell Investigation, 2025, 1, 100032
DOI: 10.1016/j.clnves.2025.100032

Fatty acid in the tumor microenvironment: Perspectives for immunotherapy

Ting Li, Yi-Ran Bie, Shan-Mei Chen, Yao Shang and Pei-Shan Hu

Critical Reviews in Oncology/Hematology, 2025, 215, 104878
DOI: 10.1016/j.critrevonc.2025.104878

Protein acylation: mechanisms, biological functions and therapeutic targets

Shuang Shang, Jing Liu and Fang Hua

Sig Transduct Target Ther, 2022, 7
DOI: 10.1038/s41392-022-01245-y

Cabozantinib enhances CAIX specific CAR-T cells against renal cancer by improving effector functions and augmenting tumor immune microenvironment

Qihong Li, Lin Yang, Shuyu Li, Wanxin Zhao, Ying Xue, Zhuyu Lu, Jingwei Tang, Xiaoge Gao, Junnian Zheng, Qing Zhang and Shishuo Sun

Biochemical and Biophysical Research Communications, 2024, 734, 150781
DOI: 10.1016/j.bbrc.2024.150781

Distinct antibody clones detect PD-1 checkpoint expression and block PD-L1 interactions on live murine melanoma cells

Christina Martins, Mariana Silva, Erik Rasbach, Praveen Singh, Yuta Itoh, Jason B. Williams, Edith Statham, Anna Meurer, Daniela V. Martinez, Anne Brandenburg, Markus V. Heppt, Steven R. Barthel and Tobias Schatton

Sci Rep, 2022, 12
DOI: 10.1038/s41598-022-16776-1

Development of an Acrylamide-Based Inhibitor of Protein S-Acylation

Saara-Anne Azizi, Tong Lan, Clémence Delalande, Rahul S. Kathayat, Fernando Banales Mejia, Alice Qin, Noah Brookes, Perla Jasmine Sandoval and Bryan C. Dickinson

ACS Chem. Biol., 2021, 16, 1546
DOI: 10.1021/acschembio.1c00405

Role of S-palmitoylation in digestive system diseases

Hanqing Li, Qiuxiang Yuan, Shuangshuang Wang, Tao Yu and Xingsi Qi

Cell Death Discov., 2025, 11
DOI: 10.1038/s41420-025-02629-z

Protein post-translational modifications and tumor immunity: A pan-cancer perspective

Haoling Zhang, Qilu Yan, Shuya Jiang, Dan Hu, Ping Lu, Shaowei Li, Doblin Sandai, Haolong Zhang, Wangzheqi Zhang and Chenglong Zhu

Physics of Life Reviews, 2025, 55, 142
DOI: 10.1016/j.plrev.2025.10.001

Fatty acid synthase (FASN) signalome: A molecular guide for precision oncology

Javier A. Menendez, Elisabet Cuyàs, Jose Antonio Encinar, Travis Vander Steen, Sara Verdura, Àngela Llop‐Hernández, Júlia López, Eila Serrano‐Hervás, Sílvia Osuna, Begoña Martin‐Castillo and Ruth Lupu

Molecular Oncology, 2024, 18, 479
DOI: 10.1002/1878-0261.13582

Palmitoylation of GPX4 via the targetable ZDHHC8 determines ferroptosis sensitivity and antitumor immunity

Liang Zhou, Guangyu Lian, Tao Zhou, Zhe Cai, Shuai Yang, Weining Li, Lilin Cheng, Ying Ye, Mingfeng He, Jianru Lu, Qifeng Deng, Bihui Huang, Xiaoqian Zhou, Desheng Lu, Feng Zhi and Jun Cui

Nat Cancer, 2025, 6, 768
DOI: 10.1038/s43018-025-00937-y

Rab37 mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion in lung cancer

Wan-Ting Kuo, I-Ying Kuo, Hung-Chia Hsieh, Ssu-Ting Wu, Wu-Chou Su and Yi-Ching Wang

J Biomed Sci, 2024, 31
DOI: 10.1186/s12929-024-01009-6

Protein lipidation in cancer: mechanisms, dysregulation and emerging drug targets

Edward W. Tate, Lior Soday, Ana Losada de la Lastra, Mei Wang and Hening Lin

Nat Rev Cancer, 2024, 24, 240
DOI: 10.1038/s41568-024-00666-x

Multifaceted roles of PD‐1 in tumorigenesis: From immune checkpoint to tumor cell‐intrinsic function

Huiqing Chen, Jiayu Wei, Zhen Zhu and Yongzhong Hou

Molecular Carcinogenesis, 2024, 63, 1436
DOI: 10.1002/mc.23740